Novel human proteases and polynucleotides encoding the same

ABSTRACT

Novel human polynucleotide and polypeptide sequences are disclosed that can be used in therapeutic, diagnostic, and pharmacogenomic applications.

[0001] The present application claims the benefit of U.S. Provisional Application No. 60/237,540 which was filed on Oct. 4, 2000 and is herein incorporated by reference in its entirety.

1. INTRODUCTION

[0002] The present invention relates to the discovery, identification, and characterization of novel human polynucleotides encoding proteins sharing sequence similarity with mammalian proteases. The invention encompasses the described polynucleotides, host cell expression systems, the encoded proteins, fusion proteins, polypeptides and peptides, antibodies to the encoded proteins and peptides, and genetically engineered animals that either lack or over express the disclosed sequences, antagonists and agonists of the proteins, and other compounds that modulate the expression or activity of the proteins encoded by the disclosed polynucleotides that can be used for diagnosis, drug screening, clinical trial monitoring, the treatment of diseases and disorders, and cosmetic or nutriceutical applications.

2. BACKGROUND OF THE INVENTION

[0003] Proteases cleave protein substrates as part of degradation, maturation, and secretory pathways within the body. Proteases have been associated with, inter alia, regulating development, diabetes, obesity, infertility, modulating cellular processes, and infectious disease. The protease family encompasses proven drugs and drug targets.

3. SUMMARY OF THE INVENTION

[0004] The present invention relates to the discovery, identification, and characterization of nucleotides that encode novel human proteins, and the corresponding amino acid sequences of these proteins. The novel human proteins (NHPs) described for the first time herein share structural similarity with animal proteases and particularly zinc metalloproteases.

[0005] The novel human nucleic acid (cDNA) sequences described herein, encode proteins/open reading frames (ORFs) of 1224, 980, 476, 1213, 969, and 465 amino acids in length (see SEQ ID NOS: 2, 4, 6, 8, 10, and 12 respectively).

[0006] The invention also encompasses agonists and antagonists of the described NHPs, including small molecules, large molecules, mutant NHPs, or portions thereof, that compete with native NHP, peptides, and antibodies, as well as nucleotide sequences that can be used to inhibit the expression of the described NHPs (e.g., antisense and ribozyme molecules, and open reading frame or regulatory sequence replacement constructs) or to enhance the expression of the described NHPs (e.g., expression constructs that place the described polynucleotide under the control of a strong promoter system), and transgenic animals that express a NHP sequence, or “knock-outs”(which can be conditional) that do not express a functional NHP. Knock-out mice can be produced in several ways, one of which involves the use of mouse embryonic stem cells (“ES cells”) lines that contain gene trap mutations in a murine homolog of at least one of the described NHPs. When the unique NHP sequences described in SEQ ID NOS:1-13 are “knocked-out” they provide a method of identifying phenotypic expression of the particular gene as well as a method of assigning function to previously unknown genes. In addition, animals in which the unique NHP sequences described in SEQ ID NOS:1-13 are “knocked-out” provide a unique source in which to elicit antibodies to homologous and orthologous proteins which would have been previously viewed by the immune system as “self” and therefore would have failed to elicit significant antibody responses.

[0007] Additionally, the unique NHP sequences described in SEQ ID NOS:1-13 are useful for the identification of protein coding sequence and mapping a unique gene to a particular chromosome. These sequences identify biologically verified exon splice junctions as opposed to splice junctions that may have been bioinformatically predicted from genomic sequence alone. The sequences of the present invention are also useful as additional DNA markers for restriction fragment length polymorphism (RFLP) analysis, and in forensic biology.

[0008] Further, the present invention also relates to processes for identifying compounds that modulate, i.e., act as agonists or antagonists, of NHP expression and/or NHP activity that utilize purified preparations of the described NHPs and/or NHP product, or cells expressing the same. Such compounds can be used as therapeutic agents for the treatment of any of a wide variety of symptoms associated with biological disorders or imbalances.

4. DESCRIPTION OF THE SEQUENCE LISTING AND FIGURES

[0009] The Sequence Listing provides the sequences of several NHP ORFs encoding the described NHP amino acid sequences. SEQ ID NO:13 describes a NHP ORF and flanking sequences.

5. DETAILED DESCRIPTION OF THE INVENTION

[0010] The NHP sequences described for the first time herein are novel proteins that are expressed in, inter alia, human cell lines, and human fetal brain, brain, pituitary, kidney, fetal liver, liver, prostate, testis, thyroid, adrenal gland, salivary gland, stomach, small intestine, colon, skeletal muscle, heart, placenta, mammary gland, adipose, esophagus, trachea, cervix, rectum, pericardium, hypothalamus, ovary, fetal kidney, and fetal lung cells.

[0011] The described sequences were compiled from sequence tags, genomic sequence, and cDNAs derived from human placenta, fetal tissue, prostate, thymus, and uterus mRNAs (Edge Biosystems, Gaithersburg, Md. and Clontech, Palo Alto, Calif.). The present invention encompasses the nucleotides presented in the Sequence Listing, host cells expressing such nucleotides, the expression products of such nucleotides, and: (a) nucleotides that encode mammalian homologs of the described sequences, including the specifically described NHPs, and NHP products; (b) nucleotides that encode one or more portions of a NHP that correspond to functional domains, and the polypeptide products specified by such nucleotide sequences, including but not limited to the novel regions of any active domain(s); (c) isolated nucleotides that encode mutant versions, engineered or naturally occurring, of the described NHPs in which all or a part of at least one domain is deleted or altered, and the polypeptide products specified by such nucleotide sequences, including but not limited to soluble proteins and peptides in which all or a portion of the signal sequence is deleted; (d) nucleotides that encode chimeric fusion proteins containing all or a portion of a coding region of a NHP, or one of its domains (e.g., a receptor or ligand binding domain, accessory protein/self-association domain, etc.) fused to another peptide or polypeptide; or (e) therapeutic or diagnostic derivatives of the described polynucleotides such as oligonucleotides, antisense polynucleotides, ribozymes, dsRNA, or gene therapy constructs comprising a sequence first disclosed in the Sequence Listing.

[0012] As discussed above, the present invention includes: (a) the human DNA sequences presented in the Sequence Listing (and vectors comprising the same) and additionally contemplates any nucleotide sequence encoding a contiguous NHP open reading frame (ORF), or a contiguous exon splice junction first described in the Sequence Listing, that hybridizes to a complement of a DNA sequence presented in the Sequence Listing under highly stringent conditions, e.g., hybridization to filter-bound DNA in 0.5 M NaHPO₄, 7% sodium dodecyl sulfate (SDS), 1 mM EDTA at 65° C., and washing in 0.1 ×SSC/0.1% SDS at 68° C. (Ausubel F. M. et al., eds., 1989, Current Protocols in Molecular Biology, Vol. I, Green Publishing Associates, Inc., and John Wiley & Sons, Inc., New York, at p. 2.10.3) and encodes a functionally equivalent expression product. Additionally contemplated are any nucleotide sequences that hybridize to the complement of the DNA sequence that encode and express an amino acid sequence presented in the Sequence Listing under moderately stringent conditions, e.g., washing in 0.2×SSC/0.1% SDS at 42° C. (Ausubel et al., 1989, supra), yet still encode a functionally equivalent NHP product. Functional equivalents of a NHP include naturally occurring NHPs present in other species and mutant NHPs whether naturally occurring or engineered (by site directed mutagenesis, gene shuffling, directed evolution as described in, for example, U.S. Pat. No. 5,837,458). The invention also includes degenerate nucleic acid variants of the disclosed NHP polynucleotide sequences.

[0013] Additionally contemplated are polynucleotides encoding a NHP ORF, or its functional equivalent, encoded by a polynucleotide sequence that is about 99, 95, 90, or about 85 percent similar or identical to corresponding regions of the nucleotide sequences of the Sequence Listing (as measured by BLAST sequence comparison analysis using, for example, the GCG sequence analysis package using standard default settings).

[0014] The invention also includes nucleic acid molecules, preferably DNA molecules, that hybridize to, and are therefore the complements of, the described NHP nucleotide sequences. Such hybridization conditions may be highly stringent or less highly stringent, as described above. In instances where the nucleic acid molecules are deoxyoligonucleotides (“DNA oligos”), such molecules are generally about 16 to about 100 bases long, or about 20 to about 80, or about 34 to about 45 bases long, or any variation or combination of sizes represented therein that incorporate a contiguous region of sequence first disclosed in the Sequence Listing. Such oligonucleotides can be used in conjunction with the polymerase chain reaction (PCR) to screen libraries, isolate clones, and prepare cloning and sequencing templates, etc.

[0015] Alternatively, such NHP oligonucleotides can be used as hybridization probes for screening libraries, and assessing gene expression patterns (particularly using a micro array or high throughout “chip” format). Additionally, a series of the described NHP oligonucleotide sequences, or the complements thereof, can be used to represent all or a portion of the described NHP sequences. An oligonucleotide or polynucleotide sequence first disclosed in at least a portion of one or more of the sequences of SEQ ID NOS: 1-13 can be used as a hybridization probe in conjunction with a solid support matrix/substrate (resins, beads, membranes, plastics, polymers, metal or metallized substrates, crystalline or polycrystalline substrates, etc.). of particular note are spatially addressable arrays (i.e., gene chips, microtiter plates, etc.) of oligonucleotides and polynucleotides, or corresponding oligopeptides and polypeptides, wherein at least one of the biopolymers present on the spatially addressable array comprises an oligonucleotide or polynucleotide sequence first disclosed in at least one of the sequences of SEQ ID NOS: 1-13, or an amino acid sequence encoded thereby. Methods for attaching biopolymers to, or synthesizing biopolymers on, solid support matrices, and conducting binding studies thereon are disclosed in, inter alia, U.S. Pat. Nos. 5,700,637, 5,556,752, 5,744,305, 4,631,211, 5,445,934, 5,252,743, 4,713,326, 5,424,186, and 4,689,405 the disclosures of which are herein incorporated by reference in their entirety.

[0016] Addressable arrays comprising sequences first disclosed in SEQ ID NOS:1-13 can be used to identify and characterize the temporal and tissue specific expression of a sequence. These addressable arrays incorporate oligonucleotide sequences of sufficient length to confer the required specificity, yet be within the limitations of the production technology. The length of these probes is within a range of between about 8 to about 2000 nucleotides. Preferably the probes consist of 60 nucleotides and more preferably 25 nucleotides from the sequences first disclosed in SEQ ID NOS:1-13.

[0017] For example, a series of the described oligonucleotide sequences, or the complements thereof, can be used in chip format to represent all or a portion of the described sequences. The oligonucleotides, typically between about 16 to about 40 (or any whole number within the stated range) nucleotides in length can partially overlap each other and/or the sequence may be represented using oligonucleotides that do not overlap. Accordingly, the described polynucleotide sequences shall typically comprise at least about two or three distinct oligonucleotide sequences of at least about 8 nucleotides in length that are each first disclosed in the described Sequence Listing. Such oligonucleotide sequences can begin at any nucleotide present within a sequence in the Sequence Listing and proceed in either a sense (5′-to-3′) orientation vis-a-vis the described sequence or in an antisense orientation.

[0018] Microarray-based analysis allows the discovery of broad patterns of genetic activity, providing new understanding of gene functions and generating novel and unexpected insight into transcriptional processes and biological mechanisms. The use of addressable arrays comprising sequences first disclosed in SEQ ID NOS:1-13 provides detailed information about transcriptional changes involved in a specific pathway, potentially leading to the identification of novel components or gene functions that manifest themselves as novel phenotypes.

[0019] Probes consisting of sequences first disclosed in SEQ ID NOS:1-13 can also be used in the identification, selection and validation of novel molecular targets for drug discovery. The use of these unique sequences permits the direct confirmation of drug targets and recognition of drug dependent changes in gene expression that are modulated through pathways distinct from the drugs intended target. These unique sequences therefore also have utility in defining and monitoring both drug action and toxicity.

[0020] As an example of utility, the sequences first disclosed in SEQ ID NOS:1-13 can be utilized in microarrays or other assay formats, to screen collections of genetic material from patients who have a particular medical condition. These investigations can also be carried out using the sequences first disclosed in SEQ ID NOS:1-13 in silico and by comparing previously collected genetic databases and the disclosed sequences using computer software known to those in the art.

[0021] Thus the sequences first disclosed in SEQ ID NOS:1-13 can be used to identify mutations associated with a particular disease and also as a diagnostic or prognostic assay.

[0022] Although the presently described sequences have been specifically described using nucleotide sequence, it should be appreciated that each of the sequences can uniquely be described using any of a wide variety of additional structural attributes, or combinations thereof. For example, a given sequence can be described by the net composition of the nucleotides present within a given region of the sequence in conjunction with the presence of one or more specific oligonucleotide sequence(s) first disclosed in the SEQ ID NOS: 1-13. Alternatively, a restriction map specifying the relative positions of restriction endonuclease digestion sites, or various palindromic or other specific oligonucleotide sequences can be used to structurally describe a given sequence. Such restriction maps, which are typically generated by widely available computer programs (e.g., the University of Wisconsin GCG sequence analysis package, SEQUENCHER 3.0, Gene Codes Corp., Ann Arbor, Mich., etc.), can optionally be used in conjunction with one or more discrete nucleotide sequence(s) present in the sequence that can be described by the relative position of the sequence relative to one or more additional sequence(s) or one or more restriction sites present in the disclosed sequence.

[0023] For oligonucleotide probes, highly stringent conditions may refer, e.g., to washing in 6×SSC/0.05% sodium pyrophosphate at 37° C. (for 14-base oligos), 48° C. (for 17-base oligos), 55° C. (for 20-base oligos), and 60° C. (for 23-base oligos). These nucleic acid molecules may encode or act as NHP gene antisense molecules, useful, for example, in NHP gene regulation (for and/or as antisense primers in amplification reactions of NHP nucleic acid sequences). With respect to NHP gene regulation, such techniques can be used to regulate biological functions. Further, such sequences may be used as part of ribozyme and/or triple helix sequences that are also useful for NHP gene regulation.

[0024] Inhibitory antisense or double stranded oligonucleotides can additionally comprise at least one modified base moiety which is selected from the group including but not limited to 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5- oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine.

[0025] The antisense oligonucleotide can also comprise at least one modified sugar moiety selected from the group including but not limited to arabinose, 2-fluoroarabinose, xylulose, and hexose.

[0026] In yet another embodiment, the antisense oligonucleotide will comprise at least one modified phosphate backbone selected from the group consisting of a phosphorothioate, a phosphorodithioate, a phosphoramidothioate, a phosphoramidate, a phosphordiamidate, a methylphosphonate, an alkyl phosphotriester, and a formacetal or analog thereof.

[0027] In yet another embodiment, the antisense oligonucleotide is an α-anomeric oligonucleotide. An α-anomeric oligonucleotide forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual β-units, the strands run parallel to each other (Gautier et al., 1987, Nucl. Acids Res. 15:6625-6641 ). The oligonucleotide is a 2′-0-methylribonucleotide (Inoue et al., 1987, Nucl. Acids Res. 15:6131-6148), or a chimeric RNA-DNA analogue (Inoue et al., 1987, FEBS Lett. 215:327-330). Alternatively, double stranded RNA can be used to disrupt the expression and function of a targeted NHP.

[0028] Oligonucleotides of the invention can be synthesized by standard methods known in the art, e.g. by use of an automated DNA synthesizer (such as are commercially available from Biosearch, Applied Biosystems, etc.). As examples, phosphorothioate oligonucleotides can be synthesized by the method of Stein et al. (1988, Nucl. Acids Res. 16:3209), and methylphosphonate oligonucleotides can be prepared by use of controlled pore glass polymer supports (Sarin et al., 1988, Proc. Natl. Acad. Sci. U.S.A. 85:7448-7451), etc.

[0029] Low stringency conditions are well known to those of skill in the art, and will vary predictably depending on the specific organisms from which the library and the labeled sequences are derived. For guidance regarding such conditions see, for example, Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual (and periodic updates thereof), Cold Springs Harbor Press, N.Y.; and Ausubel et al., 1989, Current Protocols in Molecular Biology, Green Publishing Associates and Wiley Interscience, N.Y.

[0030] Alternatively, suitably labeled NHP nucleotide probes can be used to screen a human genomic library using appropriately stringent conditions or by PCR. The identification and characterization of human genomic clones is helpful for identifying polymorphisms (including, but not limited to, nucleotide repeats, microsatellite alleles, single nucleotide polymorphisms, or coding single nucleotide polymorphisms), determining the genomic structure of a given locus/allele, and designing diagnostic tests. For example, sequences derived from regions adjacent to the intron/exon boundaries of the human gene can be used to design primers for use in amplification assays to detect mutations within the exons, introns, splice sites (e.g., splice acceptor and/or donor sites), etc., that can be used in diagnostics and pharmacogenomics.

[0031] For example, the present sequences can be used in restriction fragment length polymorphism (RFLP) analysis to identify specific individuals. In this technique, an individual's genomic DNA is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identification (as generally described in U.S. Pat. No. 5,272,057, incorporated herein by reference). In addition, the sequences of the present invention can be used to provide polynucleotide reagents, e.g., PCR primers, targeted to specific loci in the human genome, which can enhance the reliability of DNA-based forensic identifications by, for example, providing another “identification marker”(i.e., another DNA sequence that is unique to a particular individual). Actual base sequence information can be used for identification as an accurate alternative to patterns formed by restriction enzyme generated fragments.

[0032] Further, a NHP homolog can be isolated from nucleic acid from an organism of interest by performing PCR using two degenerate or “wobble” oligonucleotide primer pools designed on the basis of amino acid sequences within the NHP products disclosed herein. The template for the reaction may be total RNA, mRNA, and/or cDNA obtained by reverse transcription of mRNA prepared from human or non-human cell lines or tissue known or suspected to express an allele of a NHP gene. The PCR product can be subcloned and sequenced to ensure that the amplified sequences represent the sequence of the desired NHP gene. The PCR fragment can then be used to isolate a full length cDNA clone by a variety of methods. For example, the amplified fragment can be labeled and used to screen a cDNA library, such as a bacteriophage cDNA library. Alternatively, the labeled fragment can be used to isolate genomic clones via the screening of a genomic library.

[0033] PCR technology can also be used to isolate full length cDNA sequences. For example, RNA can be isolated, following standard procedures, from an appropriate cellular or tissue source (i.e., one known, or suspected, to express a NHP sequence, such as, for example, testis tissue). A reverse transcription (RT) reaction can be performed on the RNA using an oligonucleotide primer specific for the most 5′ end of the amplified fragment for the priming of first strand synthesis. The resulting RNA/DNA hybrid may then be “tailed” using a standard terminal transferase reaction, the hybrid may be digested with RNase H, and second strand synthesis may then be primed with a complementary primer. Thus, cDNA sequences upstream of the amplified fragment can be isolated. For a review of cloning strategies that can be used, see e.g., Sambrook et al., 1989, supra.

[0034] A cDNA encoding a mutant NHP sequence can be isolated, for example, by using PCR. In this case, the first cDNA strand may be synthesized by hybridizing an oligo-dT oligonucleotide to mRNA isolated from tissue known or suspected to be expressed in an individual putatively carrying a mutant NHP allele, and by extending the new strand with reverse transcriptase. The second strand of the cDNA is then synthesized using an oligonucleotide that hybridizes specifically to the 5′ end of the normal sequence. Using these two primers, the product is then amplified via PCR, optionally cloned into a suitable vector, and subjected to DNA sequence analysis through methods well known to those of skill in the art. By comparing the DNA sequence of the mutant NHP allele to that of a corresponding normal NHP allele, the mutation(s) responsible for the loss or alteration of function of the mutant NHP expression product can be ascertained.

[0035] Alternatively, a genomic library can be constructed using DNA obtained from an individual suspected of or known to carry a mutant NHP allele (e.g., a person manifesting a NHP-associated phenotype such as, for example, obesity, high blood pressure, arthritis, asthma, connective tissue disorders, infertility, etc.), or a cDNA library can be constructed using RNA from a tissue known, or suspected, to express a mutant NHP allele. A normal NHP gene, or any suitable fragment thereof, can then be labeled and used as a probe to identify the corresponding mutant NHP allele in such libraries. Clones containing mutant NHP expression sequences can then be purified and subjected to sequence analysis according to methods well known to those skilled in the art.

[0036] Additionally, an expression library can be constructed utilizing cDNA synthesized from, for example, RNA isolated from a tissue known, or suspected, to express a mutant NHP allele in an individual suspected of or known to carry such a mutant allele. In this manner, expression products made by the putatively mutant tissue can be expressed and screened using standard antibody screening techniques in conjunction with antibodies raised against normal NHP product, as described below. (For screening techniques, see, for example, Harlow, E. and Lane, eds., 1988, “Antibodies: A Laboratory Manual”, Cold Spring Harbor Press, Cold Spring Harbor.) Additionally, screening can be accomplished by screening with labeled NHP fusion proteins, such as, for example, alkaline phosphatase-NHP or NHP-alkaline phosphatase fusion proteins. In cases where a NHP mutation results in an expression product with altered function (e.g., as a result of a missense or a frameshift mutation); polclonal antibodies to NHP are likely to cross-react with a corresponding mutant NHP expression product. Library clones detected via their reaction with such labeled antibodies can be purified and subjected to sequence analysis according to methods well known in the art.

[0037] The invention also encompasses (a) DNA vectors that contain any of the foregoing NHP coding sequences and/or their complements (i.e., antisense); (b) DNA expression vectors that contain any of the foregoing NHP coding sequences operatively associated with a regulatory element that directs the expression of the coding sequences (for example, baculo virus as described in U.S. Pat. No. 5,869,336 herein incorporated by reference); (c) genetically engineered host cells that contain any of the foregoing NHP coding sequences operatively associated with a regulatory element that directs the expression of the coding sequences in the host cell; and (d) genetically engineered host cells that express an endogenous NHP sequences under the control of an exogenously introduced regulatory element (i.e., gene activation) or genetically engineered transcription factor. As used herein, regulatory elements include, but are not limited to, inducible and non-inducible promoters, enhancers, operators and other elements known to those skilled in the art that drive and regulate expression. Such regulatory elements include but are not limited to the cytomegalovirus (hCMV) immediate early gene, regulatable, viral elements (particularly retroviral LTR promoters), the early or late promoters of SV40 adenovirus, the lac system, the trp system, the TAC system, the TRC system, the major operator and promoter regions of phage lambda, the control regions of fd coat protein, the promoter for 3-phosphoglycerate kinase (PGK), the promoters of acid phosphatase, and the promoters of the yeast α-mating factors.

[0038] The present invention also encompasses antibodies and anti-idiotypic antibodies (including Fab fragments), antagonists and agonists of a NHP, as well as compounds or nucleotide constructs that inhibit expression of a NHP sequence (transcription factor inhibitors, antisense and ribozyme molecules, or gene or regulatory sequence replacement constructs), or promote the expression of a NHP (e.g., expression constructs in which NHP coding sequences are operatively associated with expression control elements such as promoters, promoter/enhancers, etc.).

[0039] The NHPs or NHP peptides, NHP fusion proteins, NHP nucleotide sequences, antibodies, antagonists and agonists can be useful for the detection of mutant NHPs or inappropriately expressed NHPs for the diagnosis of disease. The NHPs or NHP peptides, NHP fusion proteins, NHP nucleotide sequences, host cell expression systems, antibodies, antagonists, agonists and genetically engineered cells and animals can be used for screening for drugs (or high throughput screening of combinatorial libraries) effective in the treatment of the symptomatic or phenotypic manifestations of perturbing the normal function of NHP in the body. The use of engineered host cells and/or animals may offer an advantage in that such systems allow not only for the identification of compounds that bind to the endogenous receptor for a NHP, but can also identify compounds that trigger NHP-mediated activities or pathways.

[0040] Finally, the NHP products can be used as therapeutics. For example, soluble derivatives such as NHP peptides/domains corresponding to NHP, NHP fusion protein products (especially NHP-Ig fusion proteins, i.e., fusions of a NHP, or a domain of a NHP, to an IgFc), NHP antibodies and anti-idiotypic antibodies (including Fab fragments), antagonists or agonists (including compounds that modulate or act on downstream targets in a NHP-mediated pathway) can be used to directly treat diseases or disorders. For instance, the administration of an effective amount of soluble NHP, or a NHP-IgFc fusion protein or an anti-idiotypic antibody (or its Fab) that mimics a NHP could activate or effectively antagonize the endogenous NHP receptor. Nucleotide constructs encoding such NHP products can be used to genetically engineer host cells to express such products in vivo; these genetically engineered cells function as “bioreactors” in the body delivering a continuous supply of a NHP, a NHP peptide, or a NHP fusion protein to the body. Nucleotide constructs encoding functional NHP, mutant NHPs, as well as antisense and ribozyme molecules can also be used in “gene therapy” approaches for the modulation of NHP expression. Thus, the invention also encompasses pharmaceutical formulations and methods for treating biological disorders.

[0041] Various aspects of the invention are described in greater detail in the subsections below.

5.1 The NHP Sequences

[0042] The cDNA sequences and corresponding deduced amino acid sequences of the described NHPs are presented in the Sequence Listing. The NHP nucleotides were obtained from human cDNA libraries using probes and/or primers generated from human genomic sequence. Expression analysis has provided evidence that the described NHPs can be expressed a variety of human cells. The gene encoding the described NHPs is apparently present on human chromosome 5 (see GENBANK accession no. AC008528). Accordingly, the described are useful for identifying the corresponding coding region(s) of the human genome and for biologically identifying exon splice junctions.

[0043] Several polymorphisms were identified including a G/C polymorphism at the nucleotide position represented by, for example, position 149 of SEQ ID NO: 1 (which can result in a arg or pro at the corresponding sequence region represented by amino acid (aa) position 50 of, for example, SEQ ID NO:2), a G/C polymorphism at nucleotide position 176 (which can result in a gly or ala at corresponding aa position 59 of, for example, SEQ ID NO:2), a G/C polymorphism at the nucleotide position represented by, for example, position 179 of SEQ ID NO: 1 (which can result in a ser or thr at the corresponding sequence region represented by amino acid (aa) position 60 of, for example, SEQ ID NO:2), and a G/T polymorphism at nucleotide position 209 (which can result in a arg or leu at corresponding aa position 70 of, for example, SEQ ID NO:2). The present invention contemplates sequences incorporating any of the above polymorphisms, and any and all combinations and permutations thereof.

[0044] An additional application of the described novel human polynucleotide sequences is their use in the molecular mutagenesis/evolution of proteins that are at least partially encoded by the described novel sequences using, for example, polynucleotide shuffling or related methodologies. Such approaches are described in U.S. Pat. Nos. 5,830,721 and 5,837,458 which are herein incorporated by reference in their entirety.

[0045] NHP expression products can also be expressed in transgenic animals. Animals of any species, including, but not limited to, worms, mice, rats, rabbits, guinea pigs, pigs, micro-pigs, birds, goats, and non-human primates, e.g., baboons, monkeys, and chimpanzees may be used to generate NHP transgenic animals.

[0046] Any technique known in the art may be used to introduce a NHP transgene into animals to produce the founder lines of transgenic animals. Such techniques include, but are not limited to pronuclear microinjection (Hoppe, P. C. and Wagner, T. E., 1989, U.S. Pat. No. 4,873,191); retrovirus mediated gene transfer into germ lines (Van der Putten et al., 1985, Proc. Natl. Acad. Sci., USA 82:6148-6152); gene targeting in embryonic stem cells (Thompson et al., 1989, Cell 56:313-321); electroporation of embryos (Lo, 1983, Mol Cell. Biol. 3:1803-1814); and sperm-mediated gene transfer (Lavitrano et al., 1989, Cell 57:717-723); etc. For a review of such techniques, see Gordon, 1989, Transgenic Animals, Intl. Rev. Cytol. 115:171-229, which is incorporated by reference herein in its entirety.

[0047] The present invention provides for transgenic animals that carry the NHP transgene in all their cells, as well as animals which carry the transgene in some, but not all their cells, i.e., mosaic animals or somatic cell transgenic animals. The transgene may be integrated as a single transgene or in concatamers, e.g., head-to-head tandems or head-to-tail tandems. The transgene may also be selectively introduced into and activated in a particular cell type by following, for example, the teaching of Lasko et al., 1992, Proc. Natl. Acad. Sci. USA 89:6232-6236. The regulatory sequences required for such a cell-type specific activation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art.

[0048] When it is desired that a NHP transgene be integrated into the chromosomal site of the endogenous NHP sequence, gene targeting is preferred. Briefly, when such a technique is to be utilized, vectors containing some nucleotide sequences homologous to the endogenous NHP sequences are designed for the purpose of integrating, via homologous recombination with chromosomal sequences, into and disrupting the function of the nucleotide sequence of the endogenous NHP gene (i.e., “knockout” animals).

[0049] The transgene can also be selectively introduced into a particular cell type, thus inactivating the endogenous NHP gene in only that cell type, by following, for example, the teaching of Gu et al., 1994, Science, 265:103-106. The regulatory sequences required for such a cell-type specific inactivation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art.

[0050] Once transgenic animals have been generated, the expression of the recombinant NHP sequence may be assayed utilizing standard techniques. Initial screening may be accomplished by Southern blot analysis or PCR techniques to analyze animal tissues to assay whether integration of the transgene has taken place. The level of mRNA expression of the transgene in the tissues of the transgenic animals may also be assessed using techniques which include but are not limited to Northern blot analysis of tissue samples obtained from the animal, in situ hybridization analysis, and RT-PCR. Samples of NHP expressing tissue, may also be evaluated immunocytochemically using antibodies specific for the NHP transgene product.

5.2 NHPs and NHP Polypeptides

[0051] The NHPs, NHP polypeptides, NHP peptide fragments, mutated, truncated, or deleted forms of NHP, and/or NHP fusion proteins can be prepared for a variety of uses. These uses include, but are not limited to, the generation of antibodies, as reagents in diagnostic assays, the identification of other cellular expression products related to a NHP, as reagents in assays for screening for compounds that can be used as pharmaceutical reagents useful in the therapeutic treatment of mental, biological, or medical disorders and disease. The described NHPs share similarity with a variety of proteases, including, but not limited to, proteases having thrombospondin repeats, disintegrins, aggrecanases, procollagen I N-proteinase, and metalloproteinases (especially zinc metalloproteases of the ADAMTS family).

[0052] The Sequence Listing discloses the amino acid sequences encoded by the described NHP polynucleotides. The NHPs display initiator methionines in DNA sequence contexts consistent with translation initiation sites, and the ORFs display signal-like sequences near the N-terminus which can indicate that the described NHP ORFs are secreted proteins or membrane associated.

[0053] The NHP amino acid sequences of the invention include the amino acid sequences presented in the Sequence Listing as well as analogues and derivatives thereof. Further, corresponding NHP homologues from other species are encompassed by the invention. In fact, any NHPs encoded by a NHP nucleotide sequence described above are within the scope of the invention, as are any novel polynucleotide sequences encoding all or any novel portion of an amino acid sequence presented in the Sequence Listing. The degenerate nature of the genetic code is well known, and, accordingly, each amino acid presented in the Sequence Listing, is generically representative of the well known nucleic acid “triplet” codon, or in many cases codons, that can encode the amino acid. As such, as contemplated herein, the amino acid sequences presented in the Sequence Listing, when taken together with the genetic code (see, for example, Table 4-1 at page 109 of “Molecular Cell Biology”, 1986, J. Darnell et al. eds., Scientific American Books, New York, N.Y., herein incorporated by reference) are generically representative of all the various permutations and combinations of nucleic acid sequences that can encode such amino acid sequences.

[0054] The invention also encompasses proteins that are functionally equivalent to the NHPs encoded by the presently described nucleotide sequences as judged by any of a number of criteria, including, but not limited to, the ability to bind and cleave a substrate of a NHP, or the ability to effect an identical or complementary downstream pathway, or a change in cellular metabolism (e.g., proteolytic activity, ion flux, tyrosine phosphorylation, etc.). Such functionally equivalent NHP proteins include, but are not limited to, additions or substitutions of amino acid residues within the amino acid sequence encoded by the NHP nucleotide sequences described above, but which result in a silent change, thus producing a functionally equivalent expression product. Amino acid substitutions can be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved. For example, nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine; polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine; positively charged (basic) amino acids include arginine, lysine, and histidine; and negatively charged (acidic) amino acids include aspartic acid and glutamic acid.

[0055] A variety of host-expression vector systems can be used to express the NHP nucleotide sequences of the invention. Where, as in the present instance, a NHP peptide or NHP polypeptide is thought to be a soluble or secreted molecule, the peptide or polypeptide can be recovered from the culture media. Such expression systems also encompass engineered host cells that express NHP, or functional equivalent, in situ. Purification or enrichment of a NHP from such expression systems can be accomplished using appropriate detergents and lipid micelles and methods well known to those skilled in the art. However, such engineered host cells themselves may be used in situations where it is important not only to retain the structural and functional characteristics of a NHP, but to assess biological activity, e.g., in drug screening assays.

[0056] The expression systems that may be used for purposes of the invention include but are not limited to microorganisms such as bacteria (e.g., E. coli, B. subtilis) transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing NHP nucleotide sequences; yeast (e.g., Saccharomyces, Pichia) transformed with recombinant yeast expression vectors containing NHP encoding nucleotide sequences; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing NHP sequences; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing NHP nucleotide sequences; or mammalian cell systems (e.g., COS, CHO, BHK, 293, 3T3) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5K promoter).

[0057] In bacterial systems, a number of expression vectors may be advantageously selected depending upon the use intended for the NHP product being expressed. For example, when a large quantity of such a protein is to be produced for the generation of pharmaceutical compositions of and/or containing a NHP, or for raising antibodies to a NHP, vectors that direct the expression of high levels of fusion protein products that are readily purified may be desirable. Such vectors include, but are not limited, to the E. coli expression vector pUR278 (Ruther et al., 1983, EMBO J. 2:1791), in which a NHP coding sequence may be ligated individually into the vector in frame with the lacZ coding region so that a fusion protein is produced; pIN vectors (Inouye & Inouye, 1985, Nucleic Acids Res. 13:3101-3109; Van Heeke & Schuster, 1989, J. Biol. Chem. 264:5503-5509); and the like. pGEX vectors (Pharmacia or American Type Culture Collection) can also be used to express foreign polypeptides as fusion proteins with glutathione S-transferase (GST). In general, such fusion proteins are soluble and can easily be purified from lysed cells by adsorption to glutathione-agarose beads followed by elution in the presence of free glutathione. The pGEX vectors are designed to include thrombin or factor Xa protease cleavage sites so that the cloned target expression product can be released from the GST moiety.

[0058] In an insect system, Autographa californica nuclear polyhidrosis virus (AcNPV) is used as a vector to express foreign sequences. The virus grows in Spodoptera frugiperda cells. A NHP coding sequence can be cloned individually into non-essential regions (for example the polyhedrin gene) of the virus and placed under control of an AcNPV promoter (for example the polyhedrin promoter). Successful insertion of NHP coding sequence will result in inactivation of the polyhedrin gene and production of non-occluded recombinant virus (i.e., virus lacking the proteinaceous coat coded for by the polyhedrin gene). These recombinant viruses are then used to infect Spodoptera frugiperda cells in which the inserted sequence is expressed (e.g., see Smith et al., 1983, J. Virol. 46: 584; Smith, U.S. Pat. No. 4,215,051).

[0059] In mammalian host cells, a number of viral-based expression systems may be utilized. In cases where an adenovirus is used as an expression vector, the NHP nucleotide sequence of interest may be ligated to an adenovirus transcription/translation control complex, e.g., the late promoter and tripartite leader sequence. This chimeric sequence may then be inserted in the adenovirus genome by in vitro or in vivo recombination. Insertion in a non-essential region of the viral genome (e.g., region E1or E3) will result in a recombinant virus that is viable and capable of expressing a NHP product in infected hosts (e.g., See Logan & Shenk, 1984, Proc. Natl. Acad. Sci. USA 81:3655-3659 ). Specific initiation signals may also be required for efficient translation of inserted NHP nucleotide sequences. These signals include the ATG initiation codon and adjacent sequences. In cases where an entire NHP sequence or cDNA, including its own initiation codon and adjacent sequences, is inserted into the appropriate expression vector, no additional translational control signals may be needed. However, in cases where only a portion of a NHP coding sequence is inserted, exogenous translational control signals, including, perhaps, the ATG initiation codon, must be provided. Furthermore, the initiation codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (See Bitter et al., 1987, Methods in Enzymol. 153:516-544).

[0060] In addition, a host cell strain may be chosen that modulates the expression of the inserted sequences, or modifies and processes the expression product in the specific fashion desired. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of protein products may be important for the function of the protein. Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins and expression products. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the foreign protein expressed. To this end, eukaryotic host cells which possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the expression product may be used. Such mammalian host cells include, but are not limited to, CHO, VERO, BHK, HeLa, COS, MDCK, 293, 3T3, WI38, and in particular, human cell lines.

[0061] For long-term, high-yield production of recombinant proteins, stable expression is preferred. For example, cell lines which stably express the NHP sequences described above can be engineered. Rather than using expression vectors which contain viral origins of replication, host cells can be transformed with DNA controlled by appropriate expression control elements (e.g., promoter, enhancer sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker. Following the introduction of the foreign DNA, engineered cells may be allowed to grow for 1-2 days in an enriched media, and then are switched to a selective media. The selectable marker in the recombinant plasmid confers resistance to the selection and allows cells to stably integrate the plasmid into their chromosomes and grow to form foci which in turn can be cloned and expanded into cell lines. This method may advantageously be used to engineer cell lines which express a NHP product. Such engineered cell lines may be particularly useful in screening and evaluation of compounds that affect the endogenous activity of a NHP product.

[0062] A number of selection systems may be used, including but not limited to the herpes simplex virus thymidine kinase (Wigler, et al., 1977, Cell 11:223), hypoxanthine-guanine phosphoribosyltransferase (Szybalska & Szybalski, 1962, Proc. Natl. Acad. Sci. USA 48:2026), and adenine phosphoribosyltransferase (Lowy, et al., 1980, Cell 22:817) genes, which can be employed in tk-, hgprt- or aprt- cells, respectively. Also, antimetabolite resistance can be used as the basis of selection for the following genes: dhfr, which confers resistance to methotrexate (Wigler, et al., 1980, Natl. Acad. Sci. USA 77:3567; O'Hare, et al., 1981, Proc. Natl. Acad. Sci. USA 78:1527); gpt, which confers resistance to mycophenolic acid (Mulligan & Berg, 1981, Proc. Natl. Acad. Sci. USA 78:2072); neo, which confers resistance to the aminoglycoside G-418 (Colberre-Garapin, et al., 1981, J. Mol. Biol. 150:1); and hygro, which confers resistance to hygromycin (Santerre, et al., 1984, Gene 30:147).

[0063] Alternatively, any fusion protein can be readily purified by utilizing an antibody specific for the fusion protein being expressed. For example, a system described by Janknecht et al. allows for the ready purification of non-denatured fusion proteins expressed in human cell lines (Janknecht, et al., 1991, Proc. Natl. Acad. Sci. USA 88:8972-8976). In this system, the sequence of interest is subcloned into a vaccinia recombination plasmid such that the gene's open reading frame is translationally fused to an amino-terminal tag consisting of six histidine residues. Extracts from cells infected with recombinant vaccinia virus are loaded onto Ni²+-nitriloacetic acid-agarose columns and histidine-tagged proteins are selectively eluted with imidazole-containing buffers.

[0064] Also encompassed by the present invention are fusion proteins that direct the NHP to a target organ and/or facilitate transport across the membrane into the cytosol. Conjugation of NHPs to antibody molecules or their Fab fragments could be used to target cells bearing a particular epitope. Attaching the appropriate signal sequence to the NHP would also transport the NHP to the desired location within the cell. Alternatively targeting of NHP or its nucleic acid sequence might be achieved using liposome or lipid complex based delivery systems. Such technologies are described in “Liposomes:A Practical Approach”, New, R.R.C., ed., Oxford University Press, New York and in U.S. Pat. Nos. 4,594,595, 5,459,127, 5,948,767 and 6,110,490 and their respective disclosures which are herein incorporated by reference in their entirety. Additionally embodied are novel protein constructs engineered in such a way that they facilitate transport of the NHP to the target site or desired organ, where they cross the cell membrane and/or the nucleus where the NHP can exert its functional activity. This goal may be achieved by coupling of the NHP to a cytokine or other ligand that provides targeting specificity, and/or to a protein transducing domain (see generally U.S. applications Ser. No. 60/111,701 and 60/056,713, both of which are herein incorporated by reference, for examples of such transducing sequences) to facilitate passage across cellular membranes and can optionally be engineered to include nuclear localization.

5.3 Antibodies To NHP Products

[0065] Antibodies that specifically recognize one or more epitopes of a NHP, or epitopes of conserved variants of a NHP, or peptide fragments of a NHP are also encompassed by the invention. Such antibodies include but are not limited to polyclonal antibodies, monoclonal antibodies (mAbs), humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab′)₂ fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, and epitope-binding fragments of any of the above.

[0066] The antibodies of the invention may be used, for example, in the detection of a NHP in a biological sample and may, therefore, be utilized as part of a diagnostic or prognostic technique whereby patients may be tested for abnormal amounts of NHP. Such antibodies may also be utilized in conjunction with, for example, compound screening schemes for the evaluation of the effect of test compounds on expression and/or activity of a NHP expression product. Additionally, such antibodies can be used in conjunction gene therapy to, for example, evaluate the normal and/or engineered NHP-expressing cells prior to their introduction into the patient. Such antibodies may additionally be used as a method for the inhibition of abnormal NHP activity. Thus, such antibodies may, therefore, be utilized as part of treatment methods.

[0067] For the production of antibodies, various host animals may be immunized by injection with a NHP, an NHP peptide (e.g., one corresponding to a functional domain of a NHP), truncated NHP polypeptides (NHP in which one or more domains have been deleted), functional equivalents of a NHP or mutated variants of a NHP. Such host animals may include but are not limited to pigs, rabbits, mice, goats, and rats, to name but a few. Various adjuvants may be used to increase the immunological response, depending on the host species, including but not limited to Freund's adjuvant (complete and incomplete), mineral salts such as aluminum hydroxide or aluminum phosphate, chitosan, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, and potentially useful human adjuvants such as BCG (bacille Calmette-Guerin) and Corynebacterium parvum. Alternatively, the immune response could be enhanced by combination and or coupling with molecules such as keyhole limpet hemocyanin, tetanus toxoid, diphtheria toxoid, ovalbumin, cholera toxin or fragments thereof. Polyclonal antibodies are heterogeneous populations of antibody molecules derived from the sera of the immunized animals.

[0068] Monoclonal antibodies, which are homogeneous populations of antibodies to a particular antigen, can be obtained by any technique which provides for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, the hybridoma technique of Kohler and Milstein, (1975, Nature 256:495-497; and U.S. Pat. No. 4,376,110), the human B-cell hybridoma technique (Kosbor et al., 1983, Immunology Today 4:72; Cole et al., 1983, Proc. Natl. Acad. Sci. USA 80:2026-2030), and the EBV-hybridoma technique (Cole et al., 1985, Monoclonal Antibodies And Cancer Therapy, Alan R. Liss, Inc., pp. 77-96). Such antibodies may be of any immunoglobulin class including IgG, IgM, IgE, IgA, IgD and any subclass thereof. The hybridoma producing the mAb of this invention may be cultivated in vitro or in vivo. Production of high titers of mAbs in vivo makes this the presently preferred method of production.

[0069] In addition, techniques developed for the production of “chimeric antibodies”(Morrison et al., 1984, Proc. Natl. Acad. Sci., 81:6851-6855; Neuberger et al., 1984, Nature, 312:604-608; Takeda et al., 1985, Nature, 314:452-454) by splicing the genes from a mouse antibody molecule of appropriate antigen specificity together with genes from a human antibody molecule of appropriate biological activity can be used (see U.S. Pat. Nos. 5,877,397 and 6,075,181 herein incorporated by reference in their entirety). A chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine mAb and a human immunoglobulin constant region. Such technologies are described in U.S. Pat. Nos. 6,075,181 and 5,877,397 and their respective disclosures which are herein incorporated by reference in their entirety. Also encompassed by the present invention is the use of fully humanized monoclonal antibodies as described in U.S. Pat. No. 6,150,584 and respective disclosures which are herein incorporated by reference in their entirety.

[0070] Alternatively, techniques described for the production of single chain antibodies (U.S. Pat. 4,946,778; Bird, 1988, Science 242:423-426; Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; and Ward et al., 1989, Nature 341:544-546) can be adapted to produce single chain antibodies against NHP expression products. Single chain antibodies are formed by linking the heavy and light chain fragments of the Fv region via an amino acid bridge, resulting in a single chain polypeptide.

[0071] Antibody fragments which recognize specific epitopes may be generated by known techniques. For example, such fragments include, but are not limited to: the F(ab′)₂ fragments which can be produced by pepsin digestion of the antibody molecule and the Fab fragments which can be generated by reducing the disulfide bridges of the F(ab′)₂ fragments. Alternatively, Fab expression libraries may be constructed (Huse et al., 1989, Science, 246:1275-1281) to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity.

[0072] Antibodies to a NHP can, in turn, be utilized to generate anti-idiotype antibodies that “mimic” a given NHP, using techniques well known to those skilled in the art. (See, e.g., Greenspan & Bona, 1993, FASEB J 7(5):437-444; and Nissinoff, 1991, J. Immunol. 147(8):2429-2438). For example antibodies which bind to a NHP domain and competitively inhibit the binding of NHP to its cognate receptor can be used to generate anti-idiotypes that “mimic” a NHP and, therefore, bind and activate or neutralize a receptor. Such anti-idiotypic antibodies or Fab fragments of such anti-idiotypes can be used in therapeutic regimens involving a NHP signaling pathway.

[0073] Additionally given the high degree of relatedness of mammalian NHPs, the presently described knock-out mice (having never seen NHP, and thus never been tolerized to NHP) have a unique utility, as they can be advantageously applied to the generation of antibodies against the disclosed mammalian NHP (i.e., NHP will be immunogenic in NHP knock-out animals).

[0074] The present invention is not to be limited in scope by the specific embodiments described herein, which are intended as single illustrations of individual aspects of the invention, and functionally equivalent methods and components are within the scope of the invention. Indeed, various modifications of the invention, in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. All cited publications, patents, and patent applications are herein incorporated by reference in their entirety.

1 13 1 3675 DNA homo sapiens 1 atggggaaga accgcgagat gcgcctgact cacatctgct gctgctgcct cctttaccag 60 ctggggttcc tgtcgaatgg gatcgtttca gagctgcagt tcgcccccga ccgcgaggag 120 tgggaagtcg tgtttcctgc gctctggcgc cgggagccgg tggacccggc tggcggcagc 180 gggggcagcg cggacccggg ctgggtgcgc ggcgttgggg gcggcggaag cgcccgggcg 240 caggctgccg gcagctcacg cgaggtgcgc tctgtggctc cggtgccttt ggaggagccc 300 gtggagggcc gatcagagtc ccggctccgg cccccgccgc cgtcggaggg tgaggaggac 360 gaggagctcg agtcgcagga gctgccgcgg ggatccagcg gggctgccgc cttgtccccg 420 ggcgccccgg cctcgtggca gccgccgcct cccccgcagc cgcccccgtc cccgcccccg 480 gcccagcatg ccgagccgga tggcgacgaa gtgttgctgc ggatcccggc cttctctcgg 540 gacctgtacc tgctgctccg gagagacggc cgcttcctgg cgccgcgctt cgcagtggaa 600 cagcggccaa atcccggccc cggccccacg ggggcagcat ccgccccgca acctcccgcg 660 ccaccagacg caggctgctt ctacaccgga gctgtgctgc ggcaccctgg ctcgctggct 720 tctttcagca cctgtggagg tggcctgatg ggatttatac agctcaatga ggacttcata 780 tttattgagc cactcaatga tacaatggcc ataacaggtc acccacaccg tgtatatagg 840 cagaaaaggt ccatggagga aaaggtcaca gagaagtcag ctcttcacag tcattactgt 900 ggtatcattt cagataaagg aagacctagg tctagaaaaa tagcagaaag tggaagaggg 960 aaacgatatt catacaaatt acctcaagaa tacaacatag agactgtagt ggttgcagac 1020 ccagcaatgg tttcctatca tggagcagat gcagccagga gattcattct aaccatctta 1080 aatatggtat ttaacctttt ccaacacaag agtctgggtg tgcaggtcaa tcttcgtgtg 1140 ataaagctta ttctgctcca tgaaactcca ccagaactat atattgggca tcatggagaa 1200 aaaatgctag agagtttttg taagtggcaa catgaagaat ttggcaaaaa gaatgatata 1260 catttagaga tgtcaacaaa ctggggggaa gacatgactt cagtggatgc agctatactt 1320 ataacaagga aagatttctg tgtgcacaaa gatgaaccat gtgatactgt tggtatagct 1380 tacttgagtg gaatgtgtag tgaaaagaga aaatgtatta ttgctgaaga caatggcttg 1440 aatcttgctt ttacaattgc tcatgaaatg ggtcacaaca tgggcattaa ccatgacaat 1500 gaccacccat cgtgtgctga tggtcttcat atcatgtctg gtgaatggat taaaggacag 1560 aatcttggtg acgtttcatg gtctcgatgt agcaaggaag atttggaaag atttctcagg 1620 tcaaaggcca gtaactgctt gctacaaaca aatccgcaga gtgtcaattc tgtgatggtt 1680 ccctccaagc tgccagggat gacatacact gctgatgaac aatgccagat cctttttggg 1740 ccattggctt ctttttgtca ggagatgcag catgttattt gcacaggatt atggtgcaag 1800 gtagaaggtg agaaagaatg cagaaccaag ctagacccac caatggatgg aactgactgt 1860 gaccttggta agtggtgtaa ggctggagaa tgtaccagca ggacctcagc acctgaacat 1920 ctggccggag agtggagcct gtggagtcct tgtagccgaa cctgcagtgc tgggatcagc 1980 agtcgagagc gcaaatgtcc tgggctagat tctgaagcaa gggattgtaa tggtcccaga 2040 aaacaataca gaatatgtga gaatccacct tgtcctgcag gtttgcctgg attcagagac 2100 tggcaatgtc aggcttatag tgttagaact tcctccccaa agcatatact tcagtggcaa 2160 gctgtcctgg atgaagaaaa accatgtgcc ttgttttgct ctcctgttgg aaaagaacag 2220 cctattcttc tatcagaaaa agtgatggat ggaacttctt gtggctatca gggattagat 2280 atctgtgcaa atggcaggtg ccagaaagtt ggctgtgatg gtttattagg gtctcttgca 2340 agagaagatc attgtggtgt atgcaatggc aatggaaaat catgcaagat cattaaaggg 2400 gattttaatc acaccagagg agcaggttat gtagaagtgc tggtgatacc tgctggagca 2460 agaagaatca aagttgtgga ggaaaagccg gcacatagct atttaggtaa cctgtgttac 2520 agacacagag aagatccaac tctccgagat gctggcaaac agtctattaa tagtgactgg 2580 aagattgaac actctggagc cttcaatttg gctggaacta ccgttcatta tgtaagacga 2640 ggcctctggg agaagatctc tgccaaaggt cctactacag cacctttaca tcttctggtg 2700 ctcctgtttc aggatcagaa ttatggtctt cactatgaat acactatccc atcagaccct 2760 cttccagaaa accagagctc taaagcacct gagcccctct tcatgtggac acacacaagc 2820 tgggaagatt gcgatgccac ttgtggagga ggagaaagga agacaacagt gtcctgcaca 2880 aaaatcatga gcaaaaatat cagcattgtg gacaatgaga aatgcaaata cttaaccaag 2940 ccagagccac agattcgaaa gtgcaatgag caaccatgtc aaacaaggtg gatgatgaca 3000 gaatggaccc cttgttcacg aacttgtgga aaaggaatgc agagcagaca agtggcctgt 3060 acccaacaac tgagcaatgg aacactgatt agagcccgag agagggactg cattgggccc 3120 aagcccgcct ctgcccagcg ctgtgagggc caggactgca tgaccgtgtg ggaggcggga 3180 gtgtggtctg agtgttcagt caagtgtggc aaaggcatac gtcatcggac cgttagatgt 3240 accaacccaa gaaagaagtg tgtcctctct accagaccca gggaggctga agactgtgag 3300 gattattcaa aatgctatgt gtggcgaatg ggtgactggt ctaagtgctc aattacctgt 3360 ggcaaaggaa tgcagtcccg tgtaatccaa tgcatgcata agatcacagg aagacatgga 3420 aatgaatgtt tttcctcaga aaaacctgca gcatacaggc catgccatct tcaaccctgc 3480 aatgagaaaa ttaatgtaaa taccataaca tcacccagac tggctgctct gactttcaag 3540 tgcctgggag atcagtggcc agtgtactgc cgagtgatac gtgaaaagaa cctatgtcag 3600 gacatgcggt ggtatcagcg ctgctgtgaa acatgcaggg acttctatgc ccaaaagctg 3660 cagcagaaga gttga 3675 2 1224 PRT homo sapiens 2 Met Gly Lys Asn Arg Glu Met Arg Leu Thr His Ile Cys Cys Cys Cys 1 5 10 15 Leu Leu Tyr Gln Leu Gly Phe Leu Ser Asn Gly Ile Val Ser Glu Leu 20 25 30 Gln Phe Ala Pro Asp Arg Glu Glu Trp Glu Val Val Phe Pro Ala Leu 35 40 45 Trp Arg Arg Glu Pro Val Asp Pro Ala Gly Gly Ser Gly Gly Ser Ala 50 55 60 Asp Pro Gly Trp Val Arg Gly Val Gly Gly Gly Gly Ser Ala Arg Ala 65 70 75 80 Gln Ala Ala Gly Ser Ser Arg Glu Val Arg Ser Val Ala Pro Val Pro 85 90 95 Leu Glu Glu Pro Val Glu Gly Arg Ser Glu Ser Arg Leu Arg Pro Pro 100 105 110 Pro Pro Ser Glu Gly Glu Glu Asp Glu Glu Leu Glu Ser Gln Glu Leu 115 120 125 Pro Arg Gly Ser Ser Gly Ala Ala Ala Leu Ser Pro Gly Ala Pro Ala 130 135 140 Ser Trp Gln Pro Pro Pro Pro Pro Gln Pro Pro Pro Ser Pro Pro Pro 145 150 155 160 Ala Gln His Ala Glu Pro Asp Gly Asp Glu Val Leu Leu Arg Ile Pro 165 170 175 Ala Phe Ser Arg Asp Leu Tyr Leu Leu Leu Arg Arg Asp Gly Arg Phe 180 185 190 Leu Ala Pro Arg Phe Ala Val Glu Gln Arg Pro Asn Pro Gly Pro Gly 195 200 205 Pro Thr Gly Ala Ala Ser Ala Pro Gln Pro Pro Ala Pro Pro Asp Ala 210 215 220 Gly Cys Phe Tyr Thr Gly Ala Val Leu Arg His Pro Gly Ser Leu Ala 225 230 235 240 Ser Phe Ser Thr Cys Gly Gly Gly Leu Met Gly Phe Ile Gln Leu Asn 245 250 255 Glu Asp Phe Ile Phe Ile Glu Pro Leu Asn Asp Thr Met Ala Ile Thr 260 265 270 Gly His Pro His Arg Val Tyr Arg Gln Lys Arg Ser Met Glu Glu Lys 275 280 285 Val Thr Glu Lys Ser Ala Leu His Ser His Tyr Cys Gly Ile Ile Ser 290 295 300 Asp Lys Gly Arg Pro Arg Ser Arg Lys Ile Ala Glu Ser Gly Arg Gly 305 310 315 320 Lys Arg Tyr Ser Tyr Lys Leu Pro Gln Glu Tyr Asn Ile Glu Thr Val 325 330 335 Val Val Ala Asp Pro Ala Met Val Ser Tyr His Gly Ala Asp Ala Ala 340 345 350 Arg Arg Phe Ile Leu Thr Ile Leu Asn Met Val Phe Asn Leu Phe Gln 355 360 365 His Lys Ser Leu Gly Val Gln Val Asn Leu Arg Val Ile Lys Leu Ile 370 375 380 Leu Leu His Glu Thr Pro Pro Glu Leu Tyr Ile Gly His His Gly Glu 385 390 395 400 Lys Met Leu Glu Ser Phe Cys Lys Trp Gln His Glu Glu Phe Gly Lys 405 410 415 Lys Asn Asp Ile His Leu Glu Met Ser Thr Asn Trp Gly Glu Asp Met 420 425 430 Thr Ser Val Asp Ala Ala Ile Leu Ile Thr Arg Lys Asp Phe Cys Val 435 440 445 His Lys Asp Glu Pro Cys Asp Thr Val Gly Ile Ala Tyr Leu Ser Gly 450 455 460 Met Cys Ser Glu Lys Arg Lys Cys Ile Ile Ala Glu Asp Asn Gly Leu 465 470 475 480 Asn Leu Ala Phe Thr Ile Ala His Glu Met Gly His Asn Met Gly Ile 485 490 495 Asn His Asp Asn Asp His Pro Ser Cys Ala Asp Gly Leu His Ile Met 500 505 510 Ser Gly Glu Trp Ile Lys Gly Gln Asn Leu Gly Asp Val Ser Trp Ser 515 520 525 Arg Cys Ser Lys Glu Asp Leu Glu Arg Phe Leu Arg Ser Lys Ala Ser 530 535 540 Asn Cys Leu Leu Gln Thr Asn Pro Gln Ser Val Asn Ser Val Met Val 545 550 555 560 Pro Ser Lys Leu Pro Gly Met Thr Tyr Thr Ala Asp Glu Gln Cys Gln 565 570 575 Ile Leu Phe Gly Pro Leu Ala Ser Phe Cys Gln Glu Met Gln His Val 580 585 590 Ile Cys Thr Gly Leu Trp Cys Lys Val Glu Gly Glu Lys Glu Cys Arg 595 600 605 Thr Lys Leu Asp Pro Pro Met Asp Gly Thr Asp Cys Asp Leu Gly Lys 610 615 620 Trp Cys Lys Ala Gly Glu Cys Thr Ser Arg Thr Ser Ala Pro Glu His 625 630 635 640 Leu Ala Gly Glu Trp Ser Leu Trp Ser Pro Cys Ser Arg Thr Cys Ser 645 650 655 Ala Gly Ile Ser Ser Arg Glu Arg Lys Cys Pro Gly Leu Asp Ser Glu 660 665 670 Ala Arg Asp Cys Asn Gly Pro Arg Lys Gln Tyr Arg Ile Cys Glu Asn 675 680 685 Pro Pro Cys Pro Ala Gly Leu Pro Gly Phe Arg Asp Trp Gln Cys Gln 690 695 700 Ala Tyr Ser Val Arg Thr Ser Ser Pro Lys His Ile Leu Gln Trp Gln 705 710 715 720 Ala Val Leu Asp Glu Glu Lys Pro Cys Ala Leu Phe Cys Ser Pro Val 725 730 735 Gly Lys Glu Gln Pro Ile Leu Leu Ser Glu Lys Val Met Asp Gly Thr 740 745 750 Ser Cys Gly Tyr Gln Gly Leu Asp Ile Cys Ala Asn Gly Arg Cys Gln 755 760 765 Lys Val Gly Cys Asp Gly Leu Leu Gly Ser Leu Ala Arg Glu Asp His 770 775 780 Cys Gly Val Cys Asn Gly Asn Gly Lys Ser Cys Lys Ile Ile Lys Gly 785 790 795 800 Asp Phe Asn His Thr Arg Gly Ala Gly Tyr Val Glu Val Leu Val Ile 805 810 815 Pro Ala Gly Ala Arg Arg Ile Lys Val Val Glu Glu Lys Pro Ala His 820 825 830 Ser Tyr Leu Gly Asn Leu Cys Tyr Arg His Arg Glu Asp Pro Thr Leu 835 840 845 Arg Asp Ala Gly Lys Gln Ser Ile Asn Ser Asp Trp Lys Ile Glu His 850 855 860 Ser Gly Ala Phe Asn Leu Ala Gly Thr Thr Val His Tyr Val Arg Arg 865 870 875 880 Gly Leu Trp Glu Lys Ile Ser Ala Lys Gly Pro Thr Thr Ala Pro Leu 885 890 895 His Leu Leu Val Leu Leu Phe Gln Asp Gln Asn Tyr Gly Leu His Tyr 900 905 910 Glu Tyr Thr Ile Pro Ser Asp Pro Leu Pro Glu Asn Gln Ser Ser Lys 915 920 925 Ala Pro Glu Pro Leu Phe Met Trp Thr His Thr Ser Trp Glu Asp Cys 930 935 940 Asp Ala Thr Cys Gly Gly Gly Glu Arg Lys Thr Thr Val Ser Cys Thr 945 950 955 960 Lys Ile Met Ser Lys Asn Ile Ser Ile Val Asp Asn Glu Lys Cys Lys 965 970 975 Tyr Leu Thr Lys Pro Glu Pro Gln Ile Arg Lys Cys Asn Glu Gln Pro 980 985 990 Cys Gln Thr Arg Trp Met Met Thr Glu Trp Thr Pro Cys Ser Arg Thr 995 1000 1005 Cys Gly Lys Gly Met Gln Ser Arg Gln Val Ala Cys Thr Gln Gln Leu 1010 1015 1020 Ser Asn Gly Thr Leu Ile Arg Ala Arg Glu Arg Asp Cys Ile Gly Pro 1025 1030 1035 1040 Lys Pro Ala Ser Ala Gln Arg Cys Glu Gly Gln Asp Cys Met Thr Val 1045 1050 1055 Trp Glu Ala Gly Val Trp Ser Glu Cys Ser Val Lys Cys Gly Lys Gly 1060 1065 1070 Ile Arg His Arg Thr Val Arg Cys Thr Asn Pro Arg Lys Lys Cys Val 1075 1080 1085 Leu Ser Thr Arg Pro Arg Glu Ala Glu Asp Cys Glu Asp Tyr Ser Lys 1090 1095 1100 Cys Tyr Val Trp Arg Met Gly Asp Trp Ser Lys Cys Ser Ile Thr Cys 1105 1110 1115 1120 Gly Lys Gly Met Gln Ser Arg Val Ile Gln Cys Met His Lys Ile Thr 1125 1130 1135 Gly Arg His Gly Asn Glu Cys Phe Ser Ser Glu Lys Pro Ala Ala Tyr 1140 1145 1150 Arg Pro Cys His Leu Gln Pro Cys Asn Glu Lys Ile Asn Val Asn Thr 1155 1160 1165 Ile Thr Ser Pro Arg Leu Ala Ala Leu Thr Phe Lys Cys Leu Gly Asp 1170 1175 1180 Gln Trp Pro Val Tyr Cys Arg Val Ile Arg Glu Lys Asn Leu Cys Gln 1185 1190 1195 1200 Asp Met Arg Trp Tyr Gln Arg Cys Cys Glu Thr Cys Arg Asp Phe Tyr 1205 1210 1215 Ala Gln Lys Leu Gln Gln Lys Ser 1220 3 2943 DNA homo sapiens 3 atgggatcgt ttcagatggg atttatacag ctcaatgagg acttcatatt tattgagcca 60 ctcaatgata caatggccat aacaggtcac ccacaccgtg tatataggca gaaaaggtcc 120 atggaggaaa aggtcacaga gaagtcagct cttcacagtc attactgtgg tatcatttca 180 gataaaggaa gacctaggtc tagaaaaata gcagaaagtg gaagagggaa acgatattca 240 tacaaattac ctcaagaata caacatagag actgtagtgg ttgcagaccc agcaatggtt 300 tcctatcatg gagcagatgc agccaggaga ttcattctaa ccatcttaaa tatggtattt 360 aaccttttcc aacacaagag tctgggtgtg caggtcaatc ttcgtgtgat aaagcttatt 420 ctgctccatg aaactccacc agaactatat attgggcatc atggagaaaa aatgctagag 480 agtttttgta agtggcaaca tgaagaattt ggcaaaaaga atgatataca tttagagatg 540 tcaacaaact ggggggaaga catgacttca gtggatgcag ctatacttat aacaaggaaa 600 gatttctgtg tgcacaaaga tgaaccatgt gatactgttg gtatagctta cttgagtgga 660 atgtgtagtg aaaagagaaa atgtattatt gctgaagaca atggcttgaa tcttgctttt 720 acaattgctc atgaaatggg tcacaacatg ggcattaacc atgacaatga ccacccatcg 780 tgtgctgatg gtcttcatat catgtctggt gaatggatta aaggacagaa tcttggtgac 840 gtttcatggt ctcgatgtag caaggaagat ttggaaagat ttctcaggtc aaaggccagt 900 aactgcttgc tacaaacaaa tccgcagagt gtcaattctg tgatggttcc ctccaagctg 960 ccagggatga catacactgc tgatgaacaa tgccagatcc tttttgggcc attggcttct 1020 ttttgtcagg agatgcagca tgttatttgc acaggattat ggtgcaaggt agaaggtgag 1080 aaagaatgca gaaccaagct agacccacca atggatggaa ctgactgtga ccttggtaag 1140 tggtgtaagg ctggagaatg taccagcagg acctcagcac ctgaacatct ggccggagag 1200 tggagcctgt ggagtccttg tagccgaacc tgcagtgctg ggatcagcag tcgagagcgc 1260 aaatgtcctg ggctagattc tgaagcaagg gattgtaatg gtcccagaaa acaatacaga 1320 atatgtgaga atccaccttg tcctgcaggt ttgcctggat tcagagactg gcaatgtcag 1380 gcttatagtg ttagaacttc ctccccaaag catatacttc agtggcaagc tgtcctggat 1440 gaagaaaaac catgtgcctt gttttgctct cctgttggaa aagaacagcc tattcttcta 1500 tcagaaaaag tgatggatgg aacttcttgt ggctatcagg gattagatat ctgtgcaaat 1560 ggcaggtgcc agaaagttgg ctgtgatggt ttattagggt ctcttgcaag agaagatcat 1620 tgtggtgtat gcaatggcaa tggaaaatca tgcaagatca ttaaagggga ttttaatcac 1680 accagaggag caggttatgt agaagtgctg gtgatacctg ctggagcaag aagaatcaaa 1740 gttgtggagg aaaagccggc acatagctat ttaggtaacc tgtgttacag acacagagaa 1800 gatccaactc tccgagatgc tggcaaacag tctattaata gtgactggaa gattgaacac 1860 tctggagcct tcaatttggc tggaactacc gttcattatg taagacgagg cctctgggag 1920 aagatctctg ccaaaggtcc tactacagca cctttacatc ttctggtgct cctgtttcag 1980 gatcagaatt atggtcttca ctatgaatac actatcccat cagaccctct tccagaaaac 2040 cagagctcta aagcacctga gcccctcttc atgtggacac acacaagctg ggaagattgc 2100 gatgccactt gtggaggagg agaaaggaag acaacagtgt cctgcacaaa aatcatgagc 2160 aaaaatatca gcattgtgga caatgagaaa tgcaaatact taaccaagcc agagccacag 2220 attcgaaagt gcaatgagca accatgtcaa acaaggtgga tgatgacaga atggacccct 2280 tgttcacgaa cttgtggaaa aggaatgcag agcagacaag tggcctgtac ccaacaactg 2340 agcaatggaa cactgattag agcccgagag agggactgca ttgggcccaa gcccgcctct 2400 gcccagcgct gtgagggcca ggactgcatg accgtgtggg aggcgggagt gtggtctgag 2460 tgttcagtca agtgtggcaa aggcatacgt catcggaccg ttagatgtac caacccaaga 2520 aagaagtgtg tcctctctac cagacccagg gaggctgaag actgtgagga ttattcaaaa 2580 tgctatgtgt ggcgaatggg tgactggtct aagtgctcaa ttacctgtgg caaaggaatg 2640 cagtcccgtg taatccaatg catgcataag atcacaggaa gacatggaaa tgaatgtttt 2700 tcctcagaaa aacctgcagc atacaggcca tgccatcttc aaccctgcaa tgagaaaatt 2760 aatgtaaata ccataacatc acccagactg gctgctctga ctttcaagtg cctgggagat 2820 cagtggccag tgtactgccg agtgatacgt gaaaagaacc tatgtcagga catgcggtgg 2880 tatcagcgct gctgtgaaac atgcagggac ttctatgccc aaaagctgca gcagaagagt 2940 tga 2943 4 980 PRT homo sapiens 4 Met Gly Ser Phe Gln Met Gly Phe Ile Gln Leu Asn Glu Asp Phe Ile 1 5 10 15 Phe Ile Glu Pro Leu Asn Asp Thr Met Ala Ile Thr Gly His Pro His 20 25 30 Arg Val Tyr Arg Gln Lys Arg Ser Met Glu Glu Lys Val Thr Glu Lys 35 40 45 Ser Ala Leu His Ser His Tyr Cys Gly Ile Ile Ser Asp Lys Gly Arg 50 55 60 Pro Arg Ser Arg Lys Ile Ala Glu Ser Gly Arg Gly Lys Arg Tyr Ser 65 70 75 80 Tyr Lys Leu Pro Gln Glu Tyr Asn Ile Glu Thr Val Val Val Ala Asp 85 90 95 Pro Ala Met Val Ser Tyr His Gly Ala Asp Ala Ala Arg Arg Phe Ile 100 105 110 Leu Thr Ile Leu Asn Met Val Phe Asn Leu Phe Gln His Lys Ser Leu 115 120 125 Gly Val Gln Val Asn Leu Arg Val Ile Lys Leu Ile Leu Leu His Glu 130 135 140 Thr Pro Pro Glu Leu Tyr Ile Gly His His Gly Glu Lys Met Leu Glu 145 150 155 160 Ser Phe Cys Lys Trp Gln His Glu Glu Phe Gly Lys Lys Asn Asp Ile 165 170 175 His Leu Glu Met Ser Thr Asn Trp Gly Glu Asp Met Thr Ser Val Asp 180 185 190 Ala Ala Ile Leu Ile Thr Arg Lys Asp Phe Cys Val His Lys Asp Glu 195 200 205 Pro Cys Asp Thr Val Gly Ile Ala Tyr Leu Ser Gly Met Cys Ser Glu 210 215 220 Lys Arg Lys Cys Ile Ile Ala Glu Asp Asn Gly Leu Asn Leu Ala Phe 225 230 235 240 Thr Ile Ala His Glu Met Gly His Asn Met Gly Ile Asn His Asp Asn 245 250 255 Asp His Pro Ser Cys Ala Asp Gly Leu His Ile Met Ser Gly Glu Trp 260 265 270 Ile Lys Gly Gln Asn Leu Gly Asp Val Ser Trp Ser Arg Cys Ser Lys 275 280 285 Glu Asp Leu Glu Arg Phe Leu Arg Ser Lys Ala Ser Asn Cys Leu Leu 290 295 300 Gln Thr Asn Pro Gln Ser Val Asn Ser Val Met Val Pro Ser Lys Leu 305 310 315 320 Pro Gly Met Thr Tyr Thr Ala Asp Glu Gln Cys Gln Ile Leu Phe Gly 325 330 335 Pro Leu Ala Ser Phe Cys Gln Glu Met Gln His Val Ile Cys Thr Gly 340 345 350 Leu Trp Cys Lys Val Glu Gly Glu Lys Glu Cys Arg Thr Lys Leu Asp 355 360 365 Pro Pro Met Asp Gly Thr Asp Cys Asp Leu Gly Lys Trp Cys Lys Ala 370 375 380 Gly Glu Cys Thr Ser Arg Thr Ser Ala Pro Glu His Leu Ala Gly Glu 385 390 395 400 Trp Ser Leu Trp Ser Pro Cys Ser Arg Thr Cys Ser Ala Gly Ile Ser 405 410 415 Ser Arg Glu Arg Lys Cys Pro Gly Leu Asp Ser Glu Ala Arg Asp Cys 420 425 430 Asn Gly Pro Arg Lys Gln Tyr Arg Ile Cys Glu Asn Pro Pro Cys Pro 435 440 445 Ala Gly Leu Pro Gly Phe Arg Asp Trp Gln Cys Gln Ala Tyr Ser Val 450 455 460 Arg Thr Ser Ser Pro Lys His Ile Leu Gln Trp Gln Ala Val Leu Asp 465 470 475 480 Glu Glu Lys Pro Cys Ala Leu Phe Cys Ser Pro Val Gly Lys Glu Gln 485 490 495 Pro Ile Leu Leu Ser Glu Lys Val Met Asp Gly Thr Ser Cys Gly Tyr 500 505 510 Gln Gly Leu Asp Ile Cys Ala Asn Gly Arg Cys Gln Lys Val Gly Cys 515 520 525 Asp Gly Leu Leu Gly Ser Leu Ala Arg Glu Asp His Cys Gly Val Cys 530 535 540 Asn Gly Asn Gly Lys Ser Cys Lys Ile Ile Lys Gly Asp Phe Asn His 545 550 555 560 Thr Arg Gly Ala Gly Tyr Val Glu Val Leu Val Ile Pro Ala Gly Ala 565 570 575 Arg Arg Ile Lys Val Val Glu Glu Lys Pro Ala His Ser Tyr Leu Gly 580 585 590 Asn Leu Cys Tyr Arg His Arg Glu Asp Pro Thr Leu Arg Asp Ala Gly 595 600 605 Lys Gln Ser Ile Asn Ser Asp Trp Lys Ile Glu His Ser Gly Ala Phe 610 615 620 Asn Leu Ala Gly Thr Thr Val His Tyr Val Arg Arg Gly Leu Trp Glu 625 630 635 640 Lys Ile Ser Ala Lys Gly Pro Thr Thr Ala Pro Leu His Leu Leu Val 645 650 655 Leu Leu Phe Gln Asp Gln Asn Tyr Gly Leu His Tyr Glu Tyr Thr Ile 660 665 670 Pro Ser Asp Pro Leu Pro Glu Asn Gln Ser Ser Lys Ala Pro Glu Pro 675 680 685 Leu Phe Met Trp Thr His Thr Ser Trp Glu Asp Cys Asp Ala Thr Cys 690 695 700 Gly Gly Gly Glu Arg Lys Thr Thr Val Ser Cys Thr Lys Ile Met Ser 705 710 715 720 Lys Asn Ile Ser Ile Val Asp Asn Glu Lys Cys Lys Tyr Leu Thr Lys 725 730 735 Pro Glu Pro Gln Ile Arg Lys Cys Asn Glu Gln Pro Cys Gln Thr Arg 740 745 750 Trp Met Met Thr Glu Trp Thr Pro Cys Ser Arg Thr Cys Gly Lys Gly 755 760 765 Met Gln Ser Arg Gln Val Ala Cys Thr Gln Gln Leu Ser Asn Gly Thr 770 775 780 Leu Ile Arg Ala Arg Glu Arg Asp Cys Ile Gly Pro Lys Pro Ala Ser 785 790 795 800 Ala Gln Arg Cys Glu Gly Gln Asp Cys Met Thr Val Trp Glu Ala Gly 805 810 815 Val Trp Ser Glu Cys Ser Val Lys Cys Gly Lys Gly Ile Arg His Arg 820 825 830 Thr Val Arg Cys Thr Asn Pro Arg Lys Lys Cys Val Leu Ser Thr Arg 835 840 845 Pro Arg Glu Ala Glu Asp Cys Glu Asp Tyr Ser Lys Cys Tyr Val Trp 850 855 860 Arg Met Gly Asp Trp Ser Lys Cys Ser Ile Thr Cys Gly Lys Gly Met 865 870 875 880 Gln Ser Arg Val Ile Gln Cys Met His Lys Ile Thr Gly Arg His Gly 885 890 895 Asn Glu Cys Phe Ser Ser Glu Lys Pro Ala Ala Tyr Arg Pro Cys His 900 905 910 Leu Gln Pro Cys Asn Glu Lys Ile Asn Val Asn Thr Ile Thr Ser Pro 915 920 925 Arg Leu Ala Ala Leu Thr Phe Lys Cys Leu Gly Asp Gln Trp Pro Val 930 935 940 Tyr Cys Arg Val Ile Arg Glu Lys Asn Leu Cys Gln Asp Met Arg Trp 945 950 955 960 Tyr Gln Arg Cys Cys Glu Thr Cys Arg Asp Phe Tyr Ala Gln Lys Leu 965 970 975 Gln Gln Lys Ser 980 5 1431 DNA homo sapiens 5 atggatggaa cttcttgtgg ctatcaggga ttagatatct gtgcaaatgg caggtgccag 60 aaagttggct gtgatggttt attagggtct cttgcaagag aagatcattg tggtgtatgc 120 aatggcaatg gaaaatcatg caagatcatt aaaggggatt ttaatcacac cagaggagca 180 ggttatgtag aagtgctggt gatacctgct ggagcaagaa gaatcaaagt tgtggaggaa 240 aagccggcac atagctattt aggtaacctg tgttacagac acagagaaga tccaactctc 300 cgagatgctg gcaaacagtc tattaatagt gactggaaga ttgaacactc tggagccttc 360 aatttggctg gaactaccgt tcattatgta agacgaggcc tctgggagaa gatctctgcc 420 aaaggtccta ctacagcacc tttacatctt ctggtgctcc tgtttcagga tcagaattat 480 ggtcttcact atgaatacac tatcccatca gaccctcttc cagaaaacca gagctctaaa 540 gcacctgagc ccctcttcat gtggacacac acaagctggg aagattgcga tgccacttgt 600 ggaggaggag aaaggaagac aacagtgtcc tgcacaaaaa tcatgagcaa aaatatcagc 660 attgtggaca atgagaaatg caaatactta accaagccag agccacagat tcgaaagtgc 720 aatgagcaac catgtcaaac aaggtggatg atgacagaat ggaccccttg ttcacgaact 780 tgtggaaaag gaatgcagag cagacaagtg gcctgtaccc aacaactgag caatggaaca 840 ctgattagag cccgagagag ggactgcatt gggcccaagc ccgcctctgc ccagcgctgt 900 gagggccagg actgcatgac cgtgtgggag gcgggagtgt ggtctgagtg ttcagtcaag 960 tgtggcaaag gcatacgtca tcggaccgtt agatgtacca acccaagaaa gaagtgtgtc 1020 ctctctacca gacccaggga ggctgaagac tgtgaggatt attcaaaatg ctatgtgtgg 1080 cgaatgggtg actggtctaa gtgctcaatt acctgtggca aaggaatgca gtcccgtgta 1140 atccaatgca tgcataagat cacaggaaga catggaaatg aatgtttttc ctcagaaaaa 1200 cctgcagcat acaggccatg ccatcttcaa ccctgcaatg agaaaattaa tgtaaatacc 1260 ataacatcac ccagactggc tgctctgact ttcaagtgcc tgggagatca gtggccagtg 1320 tactgccgag tgatacgtga aaagaaccta tgtcaggaca tgcggtggta tcagcgctgc 1380 tgtgaaacat gcagggactt ctatgcccaa aagctgcagc agaagagttg a 1431 6 476 PRT homo sapiens 6 Met Asp Gly Thr Ser Cys Gly Tyr Gln Gly Leu Asp Ile Cys Ala Asn 1 5 10 15 Gly Arg Cys Gln Lys Val Gly Cys Asp Gly Leu Leu Gly Ser Leu Ala 20 25 30 Arg Glu Asp His Cys Gly Val Cys Asn Gly Asn Gly Lys Ser Cys Lys 35 40 45 Ile Ile Lys Gly Asp Phe Asn His Thr Arg Gly Ala Gly Tyr Val Glu 50 55 60 Val Leu Val Ile Pro Ala Gly Ala Arg Arg Ile Lys Val Val Glu Glu 65 70 75 80 Lys Pro Ala His Ser Tyr Leu Gly Asn Leu Cys Tyr Arg His Arg Glu 85 90 95 Asp Pro Thr Leu Arg Asp Ala Gly Lys Gln Ser Ile Asn Ser Asp Trp 100 105 110 Lys Ile Glu His Ser Gly Ala Phe Asn Leu Ala Gly Thr Thr Val His 115 120 125 Tyr Val Arg Arg Gly Leu Trp Glu Lys Ile Ser Ala Lys Gly Pro Thr 130 135 140 Thr Ala Pro Leu His Leu Leu Val Leu Leu Phe Gln Asp Gln Asn Tyr 145 150 155 160 Gly Leu His Tyr Glu Tyr Thr Ile Pro Ser Asp Pro Leu Pro Glu Asn 165 170 175 Gln Ser Ser Lys Ala Pro Glu Pro Leu Phe Met Trp Thr His Thr Ser 180 185 190 Trp Glu Asp Cys Asp Ala Thr Cys Gly Gly Gly Glu Arg Lys Thr Thr 195 200 205 Val Ser Cys Thr Lys Ile Met Ser Lys Asn Ile Ser Ile Val Asp Asn 210 215 220 Glu Lys Cys Lys Tyr Leu Thr Lys Pro Glu Pro Gln Ile Arg Lys Cys 225 230 235 240 Asn Glu Gln Pro Cys Gln Thr Arg Trp Met Met Thr Glu Trp Thr Pro 245 250 255 Cys Ser Arg Thr Cys Gly Lys Gly Met Gln Ser Arg Gln Val Ala Cys 260 265 270 Thr Gln Gln Leu Ser Asn Gly Thr Leu Ile Arg Ala Arg Glu Arg Asp 275 280 285 Cys Ile Gly Pro Lys Pro Ala Ser Ala Gln Arg Cys Glu Gly Gln Asp 290 295 300 Cys Met Thr Val Trp Glu Ala Gly Val Trp Ser Glu Cys Ser Val Lys 305 310 315 320 Cys Gly Lys Gly Ile Arg His Arg Thr Val Arg Cys Thr Asn Pro Arg 325 330 335 Lys Lys Cys Val Leu Ser Thr Arg Pro Arg Glu Ala Glu Asp Cys Glu 340 345 350 Asp Tyr Ser Lys Cys Tyr Val Trp Arg Met Gly Asp Trp Ser Lys Cys 355 360 365 Ser Ile Thr Cys Gly Lys Gly Met Gln Ser Arg Val Ile Gln Cys Met 370 375 380 His Lys Ile Thr Gly Arg His Gly Asn Glu Cys Phe Ser Ser Glu Lys 385 390 395 400 Pro Ala Ala Tyr Arg Pro Cys His Leu Gln Pro Cys Asn Glu Lys Ile 405 410 415 Asn Val Asn Thr Ile Thr Ser Pro Arg Leu Ala Ala Leu Thr Phe Lys 420 425 430 Cys Leu Gly Asp Gln Trp Pro Val Tyr Cys Arg Val Ile Arg Glu Lys 435 440 445 Asn Leu Cys Gln Asp Met Arg Trp Tyr Gln Arg Cys Cys Glu Thr Cys 450 455 460 Arg Asp Phe Tyr Ala Gln Lys Leu Gln Gln Lys Ser 465 470 475 7 3642 DNA homo sapiens 7 atggggaaga accgcgagat gcgcctgact cacatctgct gctgctgcct cctttaccag 60 ctggggttcc tgtcgaatgg gatcgtttca gagctgcagt tcgcccccga ccgcgaggag 120 tgggaagtcg tgtttcctgc gctctggcgc cgggagccgg tggacccggc tggcggcagc 180 gggggcagcg cggacccggg ctgggtgcgc ggcgttgggg gcggcggaag cgcccgggcg 240 caggctgccg gcagctcacg cgaggtgcgc tctgtggctc cggtgccttt ggaggagccc 300 gtggagggcc gatcagagtc ccggctccgg cccccgccgc cgtcggaggg tgaggaggac 360 gaggagctcg agtcgcagga gctgccgcgg ggatccagcg gggctgccgc cttgtccccg 420 ggcgccccgg cctcgtggca gccgccgcct cccccgcagc cgcccccgtc cccgcccccg 480 gcccagcatg ccgagccgga tggcgacgaa gtgttgctgc ggatcccggc cttctctcgg 540 gacctgtacc tgctgctccg gagagacggc cgcttcctgg cgccgcgctt cgcagtggaa 600 cagcggccaa atcccggccc cggccccacg ggggcagcat ccgccccgca acctcccgcg 660 ccaccagacg caggctgctt ctacaccgga gctgtgctgc ggcaccctgg ctcgctggct 720 tctttcagca cctgtggagg tggcctgatg ggatttatac agctcaatga ggacttcata 780 tttattgagc cactcaatga tacaatggcc ataacaggtc acccacaccg tgtatatagg 840 cagaaaaggt ccatggagga aaaggtcaca gagaagtcag ctcttcacag tcattactgt 900 ggtatcattt cagataaagg aagacctagg tctagaaaaa tagcagaaag tggaagaggg 960 aaacgatatt catacaaatt acctcaagaa tacaacatag agactgtagt ggttgcagac 1020 ccagcaatgg tttcctatca tggagcagat gcagccagga gattcattct aaccatctta 1080 aatatggtat ttaacctttt ccaacacaag agtctgggtg tgcaggtcaa tcttcgtgtg 1140 ataaagctta ttctgctcca tgaaactcca ccagaactat atattgggca tcatggagaa 1200 aaaatgctag agagtttttg taagtggcaa catgaagaat ttggcaaaaa gaatgatata 1260 catttagaga tgtcaacaaa ctggggggaa gacatgactt cagtggatgc agctatactt 1320 ataacaagga aagatttctg tgtgcacaaa gatgaaccat gtgatactgt tggtatagct 1380 tacttgagtg gaatgtgtag tgaaaagaga aaatgtatta ttgctgaaga caatggcttg 1440 aatcttgctt ttacaattgc tcatgaaatg ggtcacaaca tgggcattaa ccatgacaat 1500 gaccacccat cgtgtgctga tggtcttcat atcatgtctg gtgaatggat taaaggacag 1560 aatcttggtg acgtttcatg gtctcgatgt agcaaggaag atttggaaag atttctcagg 1620 tcaaaggcca gtaactgctt gctacaaaca aatccgcaga gtgtcaattc tgtgatggtt 1680 ccctccaagc tgccagggat gacatacact gctgatgaac aatgccagat cctttttggg 1740 ccattggctt ctttttgtca ggagatgcag catgttattt gcacaggatt atggtgcaag 1800 gtagaaggtg agaaagaatg cagaaccaag ctagacccac caatggatgg aactgactgt 1860 gaccttggta agtggtgtaa ggctggagaa tgtaccagca ggacctcagc acctgaacat 1920 ctggccggag agtggagcct gtggagtcct tgtagccgaa cctgcagtgc tgggatcagc 1980 agtcgagagc gcaaatgtcc tgggctagat tctgaagcaa gggattgtaa tggtcccaga 2040 aaacaataca gaatatgtga gaatccacct tgtcctgcag gtttgcctgg attcagagac 2100 tggcaatgtc aggcttatag tgttagaact tcctccccaa agcatatact tcagtggcaa 2160 gctgtcctgg atgaagaaaa accatgtgcc ttgttttgct ctcctgttgg aaaagaacag 2220 cctattcttc tatcagaaaa agtgatggat ggaacttctt gtggctatca gggattagat 2280 atctgtgcaa atggcaggtg ccagaaagtt ggctgtgatg gtttattagg gtctcttgca 2340 agagaagatc attgtggtgt atgcaatggc aatggaaaat catgcaagat cattaaaggg 2400 gattttaatc acaccagagg agcaggttat gtagaagtgc tggtgatacc tgctggagca 2460 agaagaatca aagttgtgga ggaaaagccg gcacatagct atttagctct ccgagatgct 2520 ggcaaacagt ctattaatag tgactggaag attgaacact ctggagcctt caatttggct 2580 ggaactaccg ttcattatgt aagacgaggc ctctgggaga agatctctgc caaaggtcct 2640 actacagcac ctttacatct tctggtgctc ctgtttcagg atcagaatta tggtcttcac 2700 tatgaataca ctatcccatc agaccctctt ccagaaaacc agagctctaa agcacctgag 2760 cccctcttca tgtggacaca cacaagctgg gaagattgcg atgccacttg tggaggagga 2820 gaaaggaaga caacagtgtc ctgcacaaaa atcatgagca aaaatatcag cattgtggac 2880 aatgagaaat gcaaatactt aaccaagcca gagccacaga ttcgaaagtg caatgagcaa 2940 ccatgtcaaa caaggtggat gatgacagaa tggacccctt gttcacgaac ttgtggaaaa 3000 ggaatgcaga gcagacaagt ggcctgtacc caacaactga gcaatggaac actgattaga 3060 gcccgagaga gggactgcat tgggcccaag cccgcctctg cccagcgctg tgagggccag 3120 gactgcatga ccgtgtggga ggcgggagtg tggtctgagt gttcagtcaa gtgtggcaaa 3180 ggcatacgtc atcggaccgt tagatgtacc aacccaagaa agaagtgtgt cctctctacc 3240 agacccaggg aggctgaaga ctgtgaggat tattcaaaat gctatgtgtg gcgaatgggt 3300 gactggtcta agtgctcaat tacctgtggc aaaggaatgc agtcccgtgt aatccaatgc 3360 atgcataaga tcacaggaag acatggaaat gaatgttttt cctcagaaaa acctgcagca 3420 tacaggccat gccatcttca accctgcaat gagaaaatta atgtaaatac cataacatca 3480 cccagactgg ctgctctgac tttcaagtgc ctgggagatc agtggccagt gtactgccga 3540 gtgatacgtg aaaagaacct atgtcaggac atgcggtggt atcagcgctg ctgtgaaaca 3600 tgcagggact tctatgccca aaagctgcag cagaagagtt ga 3642 8 1213 PRT homo sapiens 8 Met Gly Lys Asn Arg Glu Met Arg Leu Thr His Ile Cys Cys Cys Cys 1 5 10 15 Leu Leu Tyr Gln Leu Gly Phe Leu Ser Asn Gly Ile Val Ser Glu Leu 20 25 30 Gln Phe Ala Pro Asp Arg Glu Glu Trp Glu Val Val Phe Pro Ala Leu 35 40 45 Trp Arg Arg Glu Pro Val Asp Pro Ala Gly Gly Ser Gly Gly Ser Ala 50 55 60 Asp Pro Gly Trp Val Arg Gly Val Gly Gly Gly Gly Ser Ala Arg Ala 65 70 75 80 Gln Ala Ala Gly Ser Ser Arg Glu Val Arg Ser Val Ala Pro Val Pro 85 90 95 Leu Glu Glu Pro Val Glu Gly Arg Ser Glu Ser Arg Leu Arg Pro Pro 100 105 110 Pro Pro Ser Glu Gly Glu Glu Asp Glu Glu Leu Glu Ser Gln Glu Leu 115 120 125 Pro Arg Gly Ser Ser Gly Ala Ala Ala Leu Ser Pro Gly Ala Pro Ala 130 135 140 Ser Trp Gln Pro Pro Pro Pro Pro Gln Pro Pro Pro Ser Pro Pro Pro 145 150 155 160 Ala Gln His Ala Glu Pro Asp Gly Asp Glu Val Leu Leu Arg Ile Pro 165 170 175 Ala Phe Ser Arg Asp Leu Tyr Leu Leu Leu Arg Arg Asp Gly Arg Phe 180 185 190 Leu Ala Pro Arg Phe Ala Val Glu Gln Arg Pro Asn Pro Gly Pro Gly 195 200 205 Pro Thr Gly Ala Ala Ser Ala Pro Gln Pro Pro Ala Pro Pro Asp Ala 210 215 220 Gly Cys Phe Tyr Thr Gly Ala Val Leu Arg His Pro Gly Ser Leu Ala 225 230 235 240 Ser Phe Ser Thr Cys Gly Gly Gly Leu Met Gly Phe Ile Gln Leu Asn 245 250 255 Glu Asp Phe Ile Phe Ile Glu Pro Leu Asn Asp Thr Met Ala Ile Thr 260 265 270 Gly His Pro His Arg Val Tyr Arg Gln Lys Arg Ser Met Glu Glu Lys 275 280 285 Val Thr Glu Lys Ser Ala Leu His Ser His Tyr Cys Gly Ile Ile Ser 290 295 300 Asp Lys Gly Arg Pro Arg Ser Arg Lys Ile Ala Glu Ser Gly Arg Gly 305 310 315 320 Lys Arg Tyr Ser Tyr Lys Leu Pro Gln Glu Tyr Asn Ile Glu Thr Val 325 330 335 Val Val Ala Asp Pro Ala Met Val Ser Tyr His Gly Ala Asp Ala Ala 340 345 350 Arg Arg Phe Ile Leu Thr Ile Leu Asn Met Val Phe Asn Leu Phe Gln 355 360 365 His Lys Ser Leu Gly Val Gln Val Asn Leu Arg Val Ile Lys Leu Ile 370 375 380 Leu Leu His Glu Thr Pro Pro Glu Leu Tyr Ile Gly His His Gly Glu 385 390 395 400 Lys Met Leu Glu Ser Phe Cys Lys Trp Gln His Glu Glu Phe Gly Lys 405 410 415 Lys Asn Asp Ile His Leu Glu Met Ser Thr Asn Trp Gly Glu Asp Met 420 425 430 Thr Ser Val Asp Ala Ala Ile Leu Ile Thr Arg Lys Asp Phe Cys Val 435 440 445 His Lys Asp Glu Pro Cys Asp Thr Val Gly Ile Ala Tyr Leu Ser Gly 450 455 460 Met Cys Ser Glu Lys Arg Lys Cys Ile Ile Ala Glu Asp Asn Gly Leu 465 470 475 480 Asn Leu Ala Phe Thr Ile Ala His Glu Met Gly His Asn Met Gly Ile 485 490 495 Asn His Asp Asn Asp His Pro Ser Cys Ala Asp Gly Leu His Ile Met 500 505 510 Ser Gly Glu Trp Ile Lys Gly Gln Asn Leu Gly Asp Val Ser Trp Ser 515 520 525 Arg Cys Ser Lys Glu Asp Leu Glu Arg Phe Leu Arg Ser Lys Ala Ser 530 535 540 Asn Cys Leu Leu Gln Thr Asn Pro Gln Ser Val Asn Ser Val Met Val 545 550 555 560 Pro Ser Lys Leu Pro Gly Met Thr Tyr Thr Ala Asp Glu Gln Cys Gln 565 570 575 Ile Leu Phe Gly Pro Leu Ala Ser Phe Cys Gln Glu Met Gln His Val 580 585 590 Ile Cys Thr Gly Leu Trp Cys Lys Val Glu Gly Glu Lys Glu Cys Arg 595 600 605 Thr Lys Leu Asp Pro Pro Met Asp Gly Thr Asp Cys Asp Leu Gly Lys 610 615 620 Trp Cys Lys Ala Gly Glu Cys Thr Ser Arg Thr Ser Ala Pro Glu His 625 630 635 640 Leu Ala Gly Glu Trp Ser Leu Trp Ser Pro Cys Ser Arg Thr Cys Ser 645 650 655 Ala Gly Ile Ser Ser Arg Glu Arg Lys Cys Pro Gly Leu Asp Ser Glu 660 665 670 Ala Arg Asp Cys Asn Gly Pro Arg Lys Gln Tyr Arg Ile Cys Glu Asn 675 680 685 Pro Pro Cys Pro Ala Gly Leu Pro Gly Phe Arg Asp Trp Gln Cys Gln 690 695 700 Ala Tyr Ser Val Arg Thr Ser Ser Pro Lys His Ile Leu Gln Trp Gln 705 710 715 720 Ala Val Leu Asp Glu Glu Lys Pro Cys Ala Leu Phe Cys Ser Pro Val 725 730 735 Gly Lys Glu Gln Pro Ile Leu Leu Ser Glu Lys Val Met Asp Gly Thr 740 745 750 Ser Cys Gly Tyr Gln Gly Leu Asp Ile Cys Ala Asn Gly Arg Cys Gln 755 760 765 Lys Val Gly Cys Asp Gly Leu Leu Gly Ser Leu Ala Arg Glu Asp His 770 775 780 Cys Gly Val Cys Asn Gly Asn Gly Lys Ser Cys Lys Ile Ile Lys Gly 785 790 795 800 Asp Phe Asn His Thr Arg Gly Ala Gly Tyr Val Glu Val Leu Val Ile 805 810 815 Pro Ala Gly Ala Arg Arg Ile Lys Val Val Glu Glu Lys Pro Ala His 820 825 830 Ser Tyr Leu Ala Leu Arg Asp Ala Gly Lys Gln Ser Ile Asn Ser Asp 835 840 845 Trp Lys Ile Glu His Ser Gly Ala Phe Asn Leu Ala Gly Thr Thr Val 850 855 860 His Tyr Val Arg Arg Gly Leu Trp Glu Lys Ile Ser Ala Lys Gly Pro 865 870 875 880 Thr Thr Ala Pro Leu His Leu Leu Val Leu Leu Phe Gln Asp Gln Asn 885 890 895 Tyr Gly Leu His Tyr Glu Tyr Thr Ile Pro Ser Asp Pro Leu Pro Glu 900 905 910 Asn Gln Ser Ser Lys Ala Pro Glu Pro Leu Phe Met Trp Thr His Thr 915 920 925 Ser Trp Glu Asp Cys Asp Ala Thr Cys Gly Gly Gly Glu Arg Lys Thr 930 935 940 Thr Val Ser Cys Thr Lys Ile Met Ser Lys Asn Ile Ser Ile Val Asp 945 950 955 960 Asn Glu Lys Cys Lys Tyr Leu Thr Lys Pro Glu Pro Gln Ile Arg Lys 965 970 975 Cys Asn Glu Gln Pro Cys Gln Thr Arg Trp Met Met Thr Glu Trp Thr 980 985 990 Pro Cys Ser Arg Thr Cys Gly Lys Gly Met Gln Ser Arg Gln Val Ala 995 1000 1005 Cys Thr Gln Gln Leu Ser Asn Gly Thr Leu Ile Arg Ala Arg Glu Arg 1010 1015 1020 Asp Cys Ile Gly Pro Lys Pro Ala Ser Ala Gln Arg Cys Glu Gly Gln 1025 1030 1035 1040 Asp Cys Met Thr Val Trp Glu Ala Gly Val Trp Ser Glu Cys Ser Val 1045 1050 1055 Lys Cys Gly Lys Gly Ile Arg His Arg Thr Val Arg Cys Thr Asn Pro 1060 1065 1070 Arg Lys Lys Cys Val Leu Ser Thr Arg Pro Arg Glu Ala Glu Asp Cys 1075 1080 1085 Glu Asp Tyr Ser Lys Cys Tyr Val Trp Arg Met Gly Asp Trp Ser Lys 1090 1095 1100 Cys Ser Ile Thr Cys Gly Lys Gly Met Gln Ser Arg Val Ile Gln Cys 1105 1110 1115 1120 Met His Lys Ile Thr Gly Arg His Gly Asn Glu Cys Phe Ser Ser Glu 1125 1130 1135 Lys Pro Ala Ala Tyr Arg Pro Cys His Leu Gln Pro Cys Asn Glu Lys 1140 1145 1150 Ile Asn Val Asn Thr Ile Thr Ser Pro Arg Leu Ala Ala Leu Thr Phe 1155 1160 1165 Lys Cys Leu Gly Asp Gln Trp Pro Val Tyr Cys Arg Val Ile Arg Glu 1170 1175 1180 Lys Asn Leu Cys Gln Asp Met Arg Trp Tyr Gln Arg Cys Cys Glu Thr 1185 1190 1195 1200 Cys Arg Asp Phe Tyr Ala Gln Lys Leu Gln Gln Lys Ser 1205 1210 9 2910 DNA homo sapiens 9 atgggatcgt ttcagatggg atttatacag ctcaatgagg acttcatatt tattgagcca 60 ctcaatgata caatggccat aacaggtcac ccacaccgtg tatataggca gaaaaggtcc 120 atggaggaaa aggtcacaga gaagtcagct cttcacagtc attactgtgg tatcatttca 180 gataaaggaa gacctaggtc tagaaaaata gcagaaagtg gaagagggaa acgatattca 240 tacaaattac ctcaagaata caacatagag actgtagtgg ttgcagaccc agcaatggtt 300 tcctatcatg gagcagatgc agccaggaga ttcattctaa ccatcttaaa tatggtattt 360 aaccttttcc aacacaagag tctgggtgtg caggtcaatc ttcgtgtgat aaagcttatt 420 ctgctccatg aaactccacc agaactatat attgggcatc atggagaaaa aatgctagag 480 agtttttgta agtggcaaca tgaagaattt ggcaaaaaga atgatataca tttagagatg 540 tcaacaaact ggggggaaga catgacttca gtggatgcag ctatacttat aacaaggaaa 600 gatttctgtg tgcacaaaga tgaaccatgt gatactgttg gtatagctta cttgagtgga 660 atgtgtagtg aaaagagaaa atgtattatt gctgaagaca atggcttgaa tcttgctttt 720 acaattgctc atgaaatggg tcacaacatg ggcattaacc atgacaatga ccacccatcg 780 tgtgctgatg gtcttcatat catgtctggt gaatggatta aaggacagaa tcttggtgac 840 gtttcatggt ctcgatgtag caaggaagat ttggaaagat ttctcaggtc aaaggccagt 900 aactgcttgc tacaaacaaa tccgcagagt gtcaattctg tgatggttcc ctccaagctg 960 ccagggatga catacactgc tgatgaacaa tgccagatcc tttttgggcc attggcttct 1020 ttttgtcagg agatgcagca tgttatttgc acaggattat ggtgcaaggt agaaggtgag 1080 aaagaatgca gaaccaagct agacccacca atggatggaa ctgactgtga ccttggtaag 1140 tggtgtaagg ctggagaatg taccagcagg acctcagcac ctgaacatct ggccggagag 1200 tggagcctgt ggagtccttg tagccgaacc tgcagtgctg ggatcagcag tcgagagcgc 1260 aaatgtcctg ggctagattc tgaagcaagg gattgtaatg gtcccagaaa acaatacaga 1320 atatgtgaga atccaccttg tcctgcaggt ttgcctggat tcagagactg gcaatgtcag 1380 gcttatagtg ttagaacttc ctccccaaag catatacttc agtggcaagc tgtcctggat 1440 gaagaaaaac catgtgcctt gttttgctct cctgttggaa aagaacagcc tattcttcta 1500 tcagaaaaag tgatggatgg aacttcttgt ggctatcagg gattagatat ctgtgcaaat 1560 ggcaggtgcc agaaagttgg ctgtgatggt ttattagggt ctcttgcaag agaagatcat 1620 tgtggtgtat gcaatggcaa tggaaaatca tgcaagatca ttaaagggga ttttaatcac 1680 accagaggag caggttatgt agaagtgctg gtgatacctg ctggagcaag aagaatcaaa 1740 gttgtggagg aaaagccggc acatagctat ttagctctcc gagatgctgg caaacagtct 1800 attaatagtg actggaagat tgaacactct ggagccttca atttggctgg aactaccgtt 1860 cattatgtaa gacgaggcct ctgggagaag atctctgcca aaggtcctac tacagcacct 1920 ttacatcttc tggtgctcct gtttcaggat cagaattatg gtcttcacta tgaatacact 1980 atcccatcag accctcttcc agaaaaccag agctctaaag cacctgagcc cctcttcatg 2040 tggacacaca caagctggga agattgcgat gccacttgtg gaggaggaga aaggaagaca 2100 acagtgtcct gcacaaaaat catgagcaaa aatatcagca ttgtggacaa tgagaaatgc 2160 aaatacttaa ccaagccaga gccacagatt cgaaagtgca atgagcaacc atgtcaaaca 2220 aggtggatga tgacagaatg gaccccttgt tcacgaactt gtggaaaagg aatgcagagc 2280 agacaagtgg cctgtaccca acaactgagc aatggaacac tgattagagc ccgagagagg 2340 gactgcattg ggcccaagcc cgcctctgcc cagcgctgtg agggccagga ctgcatgacc 2400 gtgtgggagg cgggagtgtg gtctgagtgt tcagtcaagt gtggcaaagg catacgtcat 2460 cggaccgtta gatgtaccaa cccaagaaag aagtgtgtcc tctctaccag acccagggag 2520 gctgaagact gtgaggatta ttcaaaatgc tatgtgtggc gaatgggtga ctggtctaag 2580 tgctcaatta cctgtggcaa aggaatgcag tcccgtgtaa tccaatgcat gcataagatc 2640 acaggaagac atggaaatga atgtttttcc tcagaaaaac ctgcagcata caggccatgc 2700 catcttcaac cctgcaatga gaaaattaat gtaaatacca taacatcacc cagactggct 2760 gctctgactt tcaagtgcct gggagatcag tggccagtgt actgccgagt gatacgtgaa 2820 aagaacctat gtcaggacat gcggtggtat cagcgctgct gtgaaacatg cagggacttc 2880 tatgcccaaa agctgcagca gaagagttga 2910 10 969 PRT homo sapiens 10 Met Gly Ser Phe Gln Met Gly Phe Ile Gln Leu Asn Glu Asp Phe Ile 1 5 10 15 Phe Ile Glu Pro Leu Asn Asp Thr Met Ala Ile Thr Gly His Pro His 20 25 30 Arg Val Tyr Arg Gln Lys Arg Ser Met Glu Glu Lys Val Thr Glu Lys 35 40 45 Ser Ala Leu His Ser His Tyr Cys Gly Ile Ile Ser Asp Lys Gly Arg 50 55 60 Pro Arg Ser Arg Lys Ile Ala Glu Ser Gly Arg Gly Lys Arg Tyr Ser 65 70 75 80 Tyr Lys Leu Pro Gln Glu Tyr Asn Ile Glu Thr Val Val Val Ala Asp 85 90 95 Pro Ala Met Val Ser Tyr His Gly Ala Asp Ala Ala Arg Arg Phe Ile 100 105 110 Leu Thr Ile Leu Asn Met Val Phe Asn Leu Phe Gln His Lys Ser Leu 115 120 125 Gly Val Gln Val Asn Leu Arg Val Ile Lys Leu Ile Leu Leu His Glu 130 135 140 Thr Pro Pro Glu Leu Tyr Ile Gly His His Gly Glu Lys Met Leu Glu 145 150 155 160 Ser Phe Cys Lys Trp Gln His Glu Glu Phe Gly Lys Lys Asn Asp Ile 165 170 175 His Leu Glu Met Ser Thr Asn Trp Gly Glu Asp Met Thr Ser Val Asp 180 185 190 Ala Ala Ile Leu Ile Thr Arg Lys Asp Phe Cys Val His Lys Asp Glu 195 200 205 Pro Cys Asp Thr Val Gly Ile Ala Tyr Leu Ser Gly Met Cys Ser Glu 210 215 220 Lys Arg Lys Cys Ile Ile Ala Glu Asp Asn Gly Leu Asn Leu Ala Phe 225 230 235 240 Thr Ile Ala His Glu Met Gly His Asn Met Gly Ile Asn His Asp Asn 245 250 255 Asp His Pro Ser Cys Ala Asp Gly Leu His Ile Met Ser Gly Glu Trp 260 265 270 Ile Lys Gly Gln Asn Leu Gly Asp Val Ser Trp Ser Arg Cys Ser Lys 275 280 285 Glu Asp Leu Glu Arg Phe Leu Arg Ser Lys Ala Ser Asn Cys Leu Leu 290 295 300 Gln Thr Asn Pro Gln Ser Val Asn Ser Val Met Val Pro Ser Lys Leu 305 310 315 320 Pro Gly Met Thr Tyr Thr Ala Asp Glu Gln Cys Gln Ile Leu Phe Gly 325 330 335 Pro Leu Ala Ser Phe Cys Gln Glu Met Gln His Val Ile Cys Thr Gly 340 345 350 Leu Trp Cys Lys Val Glu Gly Glu Lys Glu Cys Arg Thr Lys Leu Asp 355 360 365 Pro Pro Met Asp Gly Thr Asp Cys Asp Leu Gly Lys Trp Cys Lys Ala 370 375 380 Gly Glu Cys Thr Ser Arg Thr Ser Ala Pro Glu His Leu Ala Gly Glu 385 390 395 400 Trp Ser Leu Trp Ser Pro Cys Ser Arg Thr Cys Ser Ala Gly Ile Ser 405 410 415 Ser Arg Glu Arg Lys Cys Pro Gly Leu Asp Ser Glu Ala Arg Asp Cys 420 425 430 Asn Gly Pro Arg Lys Gln Tyr Arg Ile Cys Glu Asn Pro Pro Cys Pro 435 440 445 Ala Gly Leu Pro Gly Phe Arg Asp Trp Gln Cys Gln Ala Tyr Ser Val 450 455 460 Arg Thr Ser Ser Pro Lys His Ile Leu Gln Trp Gln Ala Val Leu Asp 465 470 475 480 Glu Glu Lys Pro Cys Ala Leu Phe Cys Ser Pro Val Gly Lys Glu Gln 485 490 495 Pro Ile Leu Leu Ser Glu Lys Val Met Asp Gly Thr Ser Cys Gly Tyr 500 505 510 Gln Gly Leu Asp Ile Cys Ala Asn Gly Arg Cys Gln Lys Val Gly Cys 515 520 525 Asp Gly Leu Leu Gly Ser Leu Ala Arg Glu Asp His Cys Gly Val Cys 530 535 540 Asn Gly Asn Gly Lys Ser Cys Lys Ile Ile Lys Gly Asp Phe Asn His 545 550 555 560 Thr Arg Gly Ala Gly Tyr Val Glu Val Leu Val Ile Pro Ala Gly Ala 565 570 575 Arg Arg Ile Lys Val Val Glu Glu Lys Pro Ala His Ser Tyr Leu Ala 580 585 590 Leu Arg Asp Ala Gly Lys Gln Ser Ile Asn Ser Asp Trp Lys Ile Glu 595 600 605 His Ser Gly Ala Phe Asn Leu Ala Gly Thr Thr Val His Tyr Val Arg 610 615 620 Arg Gly Leu Trp Glu Lys Ile Ser Ala Lys Gly Pro Thr Thr Ala Pro 625 630 635 640 Leu His Leu Leu Val Leu Leu Phe Gln Asp Gln Asn Tyr Gly Leu His 645 650 655 Tyr Glu Tyr Thr Ile Pro Ser Asp Pro Leu Pro Glu Asn Gln Ser Ser 660 665 670 Lys Ala Pro Glu Pro Leu Phe Met Trp Thr His Thr Ser Trp Glu Asp 675 680 685 Cys Asp Ala Thr Cys Gly Gly Gly Glu Arg Lys Thr Thr Val Ser Cys 690 695 700 Thr Lys Ile Met Ser Lys Asn Ile Ser Ile Val Asp Asn Glu Lys Cys 705 710 715 720 Lys Tyr Leu Thr Lys Pro Glu Pro Gln Ile Arg Lys Cys Asn Glu Gln 725 730 735 Pro Cys Gln Thr Arg Trp Met Met Thr Glu Trp Thr Pro Cys Ser Arg 740 745 750 Thr Cys Gly Lys Gly Met Gln Ser Arg Gln Val Ala Cys Thr Gln Gln 755 760 765 Leu Ser Asn Gly Thr Leu Ile Arg Ala Arg Glu Arg Asp Cys Ile Gly 770 775 780 Pro Lys Pro Ala Ser Ala Gln Arg Cys Glu Gly Gln Asp Cys Met Thr 785 790 795 800 Val Trp Glu Ala Gly Val Trp Ser Glu Cys Ser Val Lys Cys Gly Lys 805 810 815 Gly Ile Arg His Arg Thr Val Arg Cys Thr Asn Pro Arg Lys Lys Cys 820 825 830 Val Leu Ser Thr Arg Pro Arg Glu Ala Glu Asp Cys Glu Asp Tyr Ser 835 840 845 Lys Cys Tyr Val Trp Arg Met Gly Asp Trp Ser Lys Cys Ser Ile Thr 850 855 860 Cys Gly Lys Gly Met Gln Ser Arg Val Ile Gln Cys Met His Lys Ile 865 870 875 880 Thr Gly Arg His Gly Asn Glu Cys Phe Ser Ser Glu Lys Pro Ala Ala 885 890 895 Tyr Arg Pro Cys His Leu Gln Pro Cys Asn Glu Lys Ile Asn Val Asn 900 905 910 Thr Ile Thr Ser Pro Arg Leu Ala Ala Leu Thr Phe Lys Cys Leu Gly 915 920 925 Asp Gln Trp Pro Val Tyr Cys Arg Val Ile Arg Glu Lys Asn Leu Cys 930 935 940 Gln Asp Met Arg Trp Tyr Gln Arg Cys Cys Glu Thr Cys Arg Asp Phe 945 950 955 960 Tyr Ala Gln Lys Leu Gln Gln Lys Ser 965 11 1398 DNA homo sapiens 11 atggatggaa cttcttgtgg ctatcaggga ttagatatct gtgcaaatgg caggtgccag 60 aaagttggct gtgatggttt attagggtct cttgcaagag aagatcattg tggtgtatgc 120 aatggcaatg gaaaatcatg caagatcatt aaaggggatt ttaatcacac cagaggagca 180 ggttatgtag aagtgctggt gatacctgct ggagcaagaa gaatcaaagt tgtggaggaa 240 aagccggcac atagctattt agctctccga gatgctggca aacagtctat taatagtgac 300 tggaagattg aacactctgg agccttcaat ttggctggaa ctaccgttca ttatgtaaga 360 cgaggcctct gggagaagat ctctgccaaa ggtcctacta cagcaccttt acatcttctg 420 gtgctcctgt ttcaggatca gaattatggt cttcactatg aatacactat cccatcagac 480 cctcttccag aaaaccagag ctctaaagca cctgagcccc tcttcatgtg gacacacaca 540 agctgggaag attgcgatgc cacttgtgga ggaggagaaa ggaagacaac agtgtcctgc 600 acaaaaatca tgagcaaaaa tatcagcatt gtggacaatg agaaatgcaa atacttaacc 660 aagccagagc cacagattcg aaagtgcaat gagcaaccat gtcaaacaag gtggatgatg 720 acagaatgga ccccttgttc acgaacttgt ggaaaaggaa tgcagagcag acaagtggcc 780 tgtacccaac aactgagcaa tggaacactg attagagccc gagagaggga ctgcattggg 840 cccaagcccg cctctgccca gcgctgtgag ggccaggact gcatgaccgt gtgggaggcg 900 ggagtgtggt ctgagtgttc agtcaagtgt ggcaaaggca tacgtcatcg gaccgttaga 960 tgtaccaacc caagaaagaa gtgtgtcctc tctaccagac ccagggaggc tgaagactgt 1020 gaggattatt caaaatgcta tgtgtggcga atgggtgact ggtctaagtg ctcaattacc 1080 tgtggcaaag gaatgcagtc ccgtgtaatc caatgcatgc ataagatcac aggaagacat 1140 ggaaatgaat gtttttcctc agaaaaacct gcagcataca ggccatgcca tcttcaaccc 1200 tgcaatgaga aaattaatgt aaataccata acatcaccca gactggctgc tctgactttc 1260 aagtgcctgg gagatcagtg gccagtgtac tgccgagtga tacgtgaaaa gaacctatgt 1320 caggacatgc ggtggtatca gcgctgctgt gaaacatgca gggacttcta tgcccaaaag 1380 ctgcagcaga agagttga 1398 12 465 PRT homo sapiens 12 Met Asp Gly Thr Ser Cys Gly Tyr Gln Gly Leu Asp Ile Cys Ala Asn 1 5 10 15 Gly Arg Cys Gln Lys Val Gly Cys Asp Gly Leu Leu Gly Ser Leu Ala 20 25 30 Arg Glu Asp His Cys Gly Val Cys Asn Gly Asn Gly Lys Ser Cys Lys 35 40 45 Ile Ile Lys Gly Asp Phe Asn His Thr Arg Gly Ala Gly Tyr Val Glu 50 55 60 Val Leu Val Ile Pro Ala Gly Ala Arg Arg Ile Lys Val Val Glu Glu 65 70 75 80 Lys Pro Ala His Ser Tyr Leu Ala Leu Arg Asp Ala Gly Lys Gln Ser 85 90 95 Ile Asn Ser Asp Trp Lys Ile Glu His Ser Gly Ala Phe Asn Leu Ala 100 105 110 Gly Thr Thr Val His Tyr Val Arg Arg Gly Leu Trp Glu Lys Ile Ser 115 120 125 Ala Lys Gly Pro Thr Thr Ala Pro Leu His Leu Leu Val Leu Leu Phe 130 135 140 Gln Asp Gln Asn Tyr Gly Leu His Tyr Glu Tyr Thr Ile Pro Ser Asp 145 150 155 160 Pro Leu Pro Glu Asn Gln Ser Ser Lys Ala Pro Glu Pro Leu Phe Met 165 170 175 Trp Thr His Thr Ser Trp Glu Asp Cys Asp Ala Thr Cys Gly Gly Gly 180 185 190 Glu Arg Lys Thr Thr Val Ser Cys Thr Lys Ile Met Ser Lys Asn Ile 195 200 205 Ser Ile Val Asp Asn Glu Lys Cys Lys Tyr Leu Thr Lys Pro Glu Pro 210 215 220 Gln Ile Arg Lys Cys Asn Glu Gln Pro Cys Gln Thr Arg Trp Met Met 225 230 235 240 Thr Glu Trp Thr Pro Cys Ser Arg Thr Cys Gly Lys Gly Met Gln Ser 245 250 255 Arg Gln Val Ala Cys Thr Gln Gln Leu Ser Asn Gly Thr Leu Ile Arg 260 265 270 Ala Arg Glu Arg Asp Cys Ile Gly Pro Lys Pro Ala Ser Ala Gln Arg 275 280 285 Cys Glu Gly Gln Asp Cys Met Thr Val Trp Glu Ala Gly Val Trp Ser 290 295 300 Glu Cys Ser Val Lys Cys Gly Lys Gly Ile Arg His Arg Thr Val Arg 305 310 315 320 Cys Thr Asn Pro Arg Lys Lys Cys Val Leu Ser Thr Arg Pro Arg Glu 325 330 335 Ala Glu Asp Cys Glu Asp Tyr Ser Lys Cys Tyr Val Trp Arg Met Gly 340 345 350 Asp Trp Ser Lys Cys Ser Ile Thr Cys Gly Lys Gly Met Gln Ser Arg 355 360 365 Val Ile Gln Cys Met His Lys Ile Thr Gly Arg His Gly Asn Glu Cys 370 375 380 Phe Ser Ser Glu Lys Pro Ala Ala Tyr Arg Pro Cys His Leu Gln Pro 385 390 395 400 Cys Asn Glu Lys Ile Asn Val Asn Thr Ile Thr Ser Pro Arg Leu Ala 405 410 415 Ala Leu Thr Phe Lys Cys Leu Gly Asp Gln Trp Pro Val Tyr Cys Arg 420 425 430 Val Ile Arg Glu Lys Asn Leu Cys Gln Asp Met Arg Trp Tyr Gln Arg 435 440 445 Cys Cys Glu Thr Cys Arg Asp Phe Tyr Ala Gln Lys Leu Gln Gln Lys 450 455 460 Ser 465 13 4666 DNA homo sapiens 13 ggacaccaca gctctcctgc ccgcgccggg cagtcctctg cctgtccaga ggcagcactc 60 ccggctctcg gctggctgtg ggtctgtctt gtggggctcc agcactagcc tgctcggcct 120 cggaaactcc tgcagcgtcc agaacacaga aaatagactc atctcctaat tcgccaggga 180 gctcgagggc tgcggggccg cggggctgcc tcccccgctc ctcccccaac ccgaccccac 240 cccacccccg ccagggcttc ggcggcctcc cggagtcaca cagcctaccc ccccacccca 300 acaccccctc ccccggcaga caaagggcct gggcaaattc gccgcccggc ctcctagcgc 360 tccggggagg ccgctgcgcc ccggagtgga tcgcgctgga ggcgtgcgcc gggcgagaag 420 ccgcggccgc gggagcgcag tatggggaag aaccgcgaga tgcgcctgac tcacatctgc 480 tgctgctgcc tcctttacca gctggggttc ctgtcgaatg ggatcgtttc agagctgcag 540 ttcgcccccg accgcgagga gtgggaagtc gtgtttcctg cgctctggcg ccgggagccg 600 gtggacccgg ctggcggcag cgggggcagc gcggacccgg gctgggtgcg cggcgttggg 660 ggcggcggaa gcgcccgggc gcaggctgcc ggcagctcac gcgaggtgcg ctctgtggct 720 ccggtgcctt tggaggagcc cgtggagggc cgatcagagt cccggctccg gcccccgccg 780 ccgtcggagg gtgaggagga cgaggagctc gagtcgcagg agctgccgcg gggatccagc 840 ggggctgccg ccttgtcccc gggcgccccg gcctcgtggc agccgccgcc tcccccgcag 900 ccgcccccgt ccccgccccc ggcccagcat gccgagccgg atggcgacga agtgttgctg 960 cggatcccgg ccttctctcg ggacctgtac ctgctgctcc ggagagacgg ccgcttcctg 1020 gcgccgcgct tcgcagtgga acagcggcca aatcccggcc ccggccccac gggggcagca 1080 tccgccccgc aacctcccgc gccaccagac gcaggctgct tctacaccgg agctgtgctg 1140 cggcaccctg gctcgctggc ttctttcagc acctgtggag gtggcctgat gggatttata 1200 cagctcaatg aggacttcat atttattgag ccactcaatg atacaatggc cataacaggt 1260 cacccacacc gtgtatatag gcagaaaagg tccatggagg aaaaggtcac agagaagtca 1320 gctcttcaca gtcattactg tggtatcatt tcagataaag gaagacctag gtctagaaaa 1380 atagcagaaa gtggaagagg gaaacgatat tcatacaaat tacctcaaga atacaacata 1440 gagactgtag tggttgcaga cccagcaatg gtttcctatc atggagcaga tgcagccagg 1500 agattcattc taaccatctt aaatatggta tttaaccttt tccaacacaa gagtctgggt 1560 gtgcaggtca atcttcgtgt gataaagctt attctgctcc atgaaactcc accagaacta 1620 tatattgggc atcatggaga aaaaatgcta gagagttttt gtaagtggca acatgaagaa 1680 tttggcaaaa agaatgatat acatttagag atgtcaacaa actgggggga agacatgact 1740 tcagtggatg cagctatact tataacaagg aaagatttct gtgtgcacaa agatgaacca 1800 tgtgatactg ttggtatagc ttacttgagt ggaatgtgta gtgaaaagag aaaatgtatt 1860 attgctgaag acaatggctt gaatcttgct tttacaattg ctcatgaaat gggtcacaac 1920 atgggcatta accatgacaa tgaccaccca tcgtgtgctg atggtcttca tatcatgtct 1980 ggtgaatgga ttaaaggaca gaatcttggt gacgtttcat ggtctcgatg tagcaaggaa 2040 gatttggaaa gatttctcag gtcaaaggcc agtaactgct tgctacaaac aaatccgcag 2100 agtgtcaatt ctgtgatggt tccctccaag ctgccaggga tgacatacac tgctgatgaa 2160 caatgccaga tcctttttgg gccattggct tctttttgtc aggagatgca gcatgttatt 2220 tgcacaggat tatggtgcaa ggtagaaggt gagaaagaat gcagaaccaa gctagaccca 2280 ccaatggatg gaactgactg tgaccttggt aagtggtgta aggctggaga atgtaccagc 2340 aggacctcag cacctgaaca tctggccgga gagtggagcc tgtggagtcc ttgtagccga 2400 acctgcagtg ctgggatcag cagtcgagag cgcaaatgtc ctgggctaga ttctgaagca 2460 agggattgta atggtcccag aaaacaatac agaatatgtg agaatccacc ttgtcctgca 2520 ggtttgcctg gattcagaga ctggcaatgt caggcttata gtgttagaac ttcctcccca 2580 aagcatatac ttcagtggca agctgtcctg gatgaagaaa aaccatgtgc cttgttttgc 2640 tctcctgttg gaaaagaaca gcctattctt ctatcagaaa aagtgatgga tggaacttct 2700 tgtggctatc agggattaga tatctgtgca aatggcaggt gccagaaagt tggctgtgat 2760 ggtttattag ggtctcttgc aagagaagat cattgtggtg tatgcaatgg caatggaaaa 2820 tcatgcaaga tcattaaagg ggattttaat cacaccagag gagcaggtta tgtagaagtg 2880 ctggtgatac ctgctggagc aagaagaatc aaagttgtgg aggaaaagcc ggcacatagc 2940 tatttaggta acctgtgtta cagacacaga gaagatccaa ctctccgaga tgctggcaaa 3000 cagtctatta atagtgactg gaagattgaa cactctggag ccttcaattt ggctggaact 3060 accgttcatt atgtaagacg aggcctctgg gagaagatct ctgccaaagg tcctactaca 3120 gcacctttac atcttctggt gctcctgttt caggatcaga attatggtct tcactatgaa 3180 tacactatcc catcagaccc tcttccagaa aaccagagct ctaaagcacc tgagcccctc 3240 ttcatgtgga cacacacaag ctgggaagat tgcgatgcca cttgtggagg aggagaaagg 3300 aagacaacag tgtcctgcac aaaaatcatg agcaaaaata tcagcattgt ggacaatgag 3360 aaatgcaaat acttaaccaa gccagagcca cagattcgaa agtgcaatga gcaaccatgt 3420 caaacaaggt ggatgatgac agaatggacc ccttgttcac gaacttgtgg aaaaggaatg 3480 cagagcagac aagtggcctg tacccaacaa ctgagcaatg gaacactgat tagagcccga 3540 gagagggact gcattgggcc caagcccgcc tctgcccagc gctgtgaggg ccaggactgc 3600 atgaccgtgt gggaggcggg agtgtggtct gagtgttcag tcaagtgtgg caaaggcata 3660 cgtcatcgga ccgttagatg taccaaccca agaaagaagt gtgtcctctc taccagaccc 3720 agggaggctg aagactgtga ggattattca aaatgctatg tgtggcgaat gggtgactgg 3780 tctaagtgct caattacctg tggcaaagga atgcagtccc gtgtaatcca atgcatgcat 3840 aagatcacag gaagacatgg aaatgaatgt ttttcctcag aaaaacctgc agcatacagg 3900 ccatgccatc ttcaaccctg caatgagaaa attaatgtaa ataccataac atcacccaga 3960 ctggctgctc tgactttcaa gtgcctggga gatcagtggc cagtgtactg ccgagtgata 4020 cgtgaaaaga acctatgtca ggacatgcgg tggtatcagc gctgctgtga aacatgcagg 4080 gacttctatg cccaaaagct gcagcagaag agttgacctc tagcaggctg gctggatcac 4140 agctctttgc aattacatta tttataaaca cacacactag catgtttttc agaccaaata 4200 ttatcagatt acatataatt taatcaaatt aatttatttt tttgcctgcc aaacatccaa 4260 tgtggtgctt gttttggtta cacaaacatt ttgatttata ctatatggct tcataaataa 4320 ttttatatga atgaattagt tggatccagt aatataataa aaagaaaaag gaaaaaaata 4380 gatcattata cttaaaacaa ggtttcgttg tttgttaggg ctatctctaa ggtgctactc 4440 tctccccacc aataacattg aattatccag aatgtatact gacttagcat aatagtttag 4500 gtgtatatga agagaaacta tttttgtttt ttggtgtcct gctgcagaat tagcccattt 4560 tctgtcacct gcaggagatg tgtaaacata atgaacctca tgctgttgaa caggttttta 4620 agagaatgta ttatgaaatt ggttcagatt tatagacatc catagg 4666 

What is claimed is:
 1. An isolated nucleic acid molecule comprising at least 24 contiguous bases of nucleotide sequence first disclosed in the sequence described in SEQ ID NO:
 1. 2. An isolated nucleic acid molecule comprising a nucleotide sequence that: (a) encodes the amino acid sequence shown in SEQ ID NO: 2; and (b) hybridizes under stringent conditions to the nucleotide sequence of SEQ ID NO: 1 or the complement thereof.
 3. An isolated nucleic acid molecule comprising a nucleotide sequence encoding an amino acid sequence drawn from the group consisting of SEQ ID NOS: 2, 4, 6, 8, 10, and
 12. 4. An isolated nucleic acid molecule comprising a sequence encoding the amino acid sequence presented in SEQ ID NO:2.
 5. An isolated nucleic acid molecule comprising a sequence encoding the amino acid sequence presented in SEQ ID NO:4.
 6. An isolated nucleic acid molecule comprising a sequence encoding the amino acid sequence presented in SEQ ID NO:10. 